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Mahmoud H. El Kouni - One of the best experts on this subject based on the ideXlab platform.
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Uridine prevents the glucose deprivation-induced death of immunostimulated astrocytes via the action of Uridine phosphorylase
Neuroscience Research, 2006Co-Authors: Ji-woong Choi, Chan Young Shin, Mahmoud H. El Kouni, Kwang Ho KoAbstract:We previously reported that in immunostimulated astrocytes, glucose deprivation induced cell death via the loss of ATP, reduced glutathione, and mitochondrial transmembrane potential. The cytotoxicity was due to reactive nitrogen and oxygen species and blocked by adenosine, a purine nucleoside, via the preservation of cellular ATP. Here, we investigated whether Uridine, a pyrimidine nucleoside, could prevent the glucose deprivation-induced cytotoxicity in LPS + IFN-γ-treated (immunostimulated) astrocytes. Glucose deprivation induced the death of immunostimulated cells, which was significantly reduced by Uridine. Glucose deprivation rapidly decreased cellular ATP levels in immunostimulated astrocytes, which was also reversed by Uridine. The inhibition of cellular uptake of Uridine by S-(4-nitrobenzyl)-6-thioinosine attenuated the protective effect of Uridine. mRNA and protein expression for Uridine phosphorylase, an enzyme catalyzing reversible phosphorolysis of Uridine, were observed in rat brain as well as primary astrocytes. 5-(Phenylthio)acycloUridine (PTAU), a specific inhibitor of Uridine phosphorylase, inhibited the protective effect of Uridine. Additionally, the loss of mitochondrial transmembrane potential and reduced glutathione by glucose deprivation in immunostimulated cells was attenuated by Uridine, which was also reversed by PTAU. These results provide the first evidence that Uridine protects immunostimulated astrocytes against the glucose deprivation-induced death by preserving intracellular ATP through the action of Uridine phosphorylase.
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Enhancement of the bioavailability of oral Uridine by coadministration of 5-(phenylthio)acycloUridine, a Uridine phosphorylase inhibitor: implications for Uridine rescue regimens in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Omar N. Al Safarjalani, Xiao-jian Zhou, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acycloUridine (PTAU) in improving the oral bioavailability of Uridine. PTAU is a new potent and specific inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in Uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). Methods: PTAU was administered orally to mice alone or with Uridine. The plasma levels of PTAU as well as those of Uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. Results: Coadministration of PTAU with Uridine elevated the concentration of plasma Uridine in a dose-dependent manner over that resulting from the administration of the same dose of Uridine alone, and reduced the clearance of Uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of Uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 µmol·h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of Uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg Uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg Uridine by 2.2-, 2.6- and 3.2-fold, respectively. Conclusion: The effectiveness of PTAU in improving the oral bioavailability of Uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of Uridine.
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Effect of 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase, on plasma concentration of Uridine released from 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine: relevance to Uridine rescue in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acycloUridine (PSAU) with 2′,3′,5′-tri-O-acetylUridine (TAU) on the levels of plasma Uridine in mice. PSAU is a new lipophilic and potent inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral Uridine. TAU is a prodrug of Uridine and a far superior source of Uridine than Uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of Uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma Uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma Uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma Uridine concentration could be useful in the management of medical disorders that are remedied by administration of Uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.
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Modulation of plasma Uridine concentration by 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase: relevance to chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Omar N. Al Safarjalani, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acycloUridine (PSAU) in increasing endogenous plasma Uridine concentration as well as its ability to improve the bioavailability of oral Uridine. PSAU is a new potent and specific inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in Uridine catabolism. Methods: Oral PSAU was administered orally to mice alone or with Uridine. The plasma levels of PSAU as well as Uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma Uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with Uridine elevated the concentration of plasma Uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral Uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of Uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg Uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg Uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg Uridine was used. Conclusion: The effectiveness of the PSAU plus Uridine combination in elevating and sustaining high plasma Uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of Uridine.
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5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a Uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine, as modulators of plasma Uridine concentration. Implications for chemotherapy.
Biochemical Pharmacology, 1996Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism, and 2',3',5'-tri-O-acetylUridine (TAU), a prodrug of Uridine, were used to investigate the possibility of improving the bioavailability of oral Uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma Uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma Uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than Uridine in improving the bioavailability of plasma Uridine. The relative bioavailability of plasma Uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral Uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma Uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with Uridine or TAU further improved the bioavailability of plasma Uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of Uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of Uridine (1320 mg/kg) increased the relative bioavailability of oral Uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma Uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of Uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma Uridine concentration can be useful in the management of medical disorders that are remedied by administration of Uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.
Raffael Schaffrath - One of the best experts on this subject based on the ideXlab platform.
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wobble Uridine modifications a reason to live a reason to die
RNA Biology, 2017Co-Authors: Raffael Schaffrath, Sebastian A LeidelAbstract:Wobble Uridines (U34) are generally modified in all species. U34 modifications can be essential in metazoans but are not required for viability in fungi. In this review, we provide an overview on the types of modifications and how they affect the physico-chemical properties of wobble Uridines. We describe the molecular machinery required to introduce these modifications into tRNA posttranscriptionally and discuss how posttranslational regulation may affect the activity of the modifying enzymes. We highlight the activity of anticodon specific RNases that target U34 containing tRNA. Finally, we discuss how defects in wobble Uridine modifications lead to phenotypes in different species. Importantly, this review will mainly focus on the cytoplasmic tRNAs of eukaryotes. A recent review has extensively covered their bacterial and mitochondrial counterparts. 1.
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loss of anticodon wobble Uridine modifications affects trnalys function and protein levels in saccharomyces cerevisiae
PLOS ONE, 2015Co-Authors: Roland Klassen, Pia Grunewald, Kathrin Thuring, Christian Eichler, Mark Helm, Raffael SchaffrathAbstract:In eukaryotes, wobble Uridines in the anticodons of tRNALysUUU, tRNAGluUUC and tRNAGlnUUG are modified to 5-methoxy-carbonyl-methyl-2-thio-Uridine (mcm5s2U). While mutations in subunits of the Elongator complex (Elp1-Elp6), which disable mcm5 side chain formation, or removal of components of the thiolation pathway (Ncs2/Ncs6, Urm1, Uba4) are individually tolerated, the combination of both modification defects has been reported to have lethal effects on Saccharomyces cerevisiae. Contrary to such absolute requirement of mcm5s2U for viability, we demonstrate here that in the S. cerevisiae S288C-derived background, both pathways can be simultaneously inactivated, resulting in combined loss of tRNA anticodon modifications (mcm5U and s2U) without a lethal effect. However, an elp3 disruption strain displays synthetic sick interaction and synergistic temperature sensitivity when combined with either uba4 or urm1 mutations, suggesting major translational defects in the absence of mcm5s2U modifications. Consistent with this notion, we find cellular protein levels drastically decreased in an elp3uba4 double mutant and show that this effect as well as growth phenotypes can be partially rescued by excess of tRNALysUUU. These results may indicate a global translational or protein homeostasis defect in cells simultaneously lacking mcm5 and s2 wobble Uridine modification that could account for growth impairment and mainly originates from tRNALysUUU hypomodification and malfunction.
Fardos N.m. Naguib - One of the best experts on this subject based on the ideXlab platform.
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Enhancement of the bioavailability of oral Uridine by coadministration of 5-(phenylthio)acycloUridine, a Uridine phosphorylase inhibitor: implications for Uridine rescue regimens in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Omar N. Al Safarjalani, Xiao-jian Zhou, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acycloUridine (PTAU) in improving the oral bioavailability of Uridine. PTAU is a new potent and specific inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in Uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). Methods: PTAU was administered orally to mice alone or with Uridine. The plasma levels of PTAU as well as those of Uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. Results: Coadministration of PTAU with Uridine elevated the concentration of plasma Uridine in a dose-dependent manner over that resulting from the administration of the same dose of Uridine alone, and reduced the clearance of Uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of Uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 µmol·h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of Uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg Uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg Uridine by 2.2-, 2.6- and 3.2-fold, respectively. Conclusion: The effectiveness of PTAU in improving the oral bioavailability of Uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of Uridine.
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Effect of 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase, on plasma concentration of Uridine released from 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine: relevance to Uridine rescue in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acycloUridine (PSAU) with 2′,3′,5′-tri-O-acetylUridine (TAU) on the levels of plasma Uridine in mice. PSAU is a new lipophilic and potent inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral Uridine. TAU is a prodrug of Uridine and a far superior source of Uridine than Uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of Uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma Uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma Uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma Uridine concentration could be useful in the management of medical disorders that are remedied by administration of Uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.
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Modulation of plasma Uridine concentration by 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase: relevance to chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Omar N. Al Safarjalani, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acycloUridine (PSAU) in increasing endogenous plasma Uridine concentration as well as its ability to improve the bioavailability of oral Uridine. PSAU is a new potent and specific inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in Uridine catabolism. Methods: Oral PSAU was administered orally to mice alone or with Uridine. The plasma levels of PSAU as well as Uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma Uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with Uridine elevated the concentration of plasma Uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral Uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of Uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg Uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg Uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg Uridine was used. Conclusion: The effectiveness of the PSAU plus Uridine combination in elevating and sustaining high plasma Uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of Uridine.
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5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a Uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine, as modulators of plasma Uridine concentration. Implications for chemotherapy.
Biochemical Pharmacology, 1996Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism, and 2',3',5'-tri-O-acetylUridine (TAU), a prodrug of Uridine, were used to investigate the possibility of improving the bioavailability of oral Uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma Uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma Uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than Uridine in improving the bioavailability of plasma Uridine. The relative bioavailability of plasma Uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral Uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma Uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with Uridine or TAU further improved the bioavailability of plasma Uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of Uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of Uridine (1320 mg/kg) increased the relative bioavailability of oral Uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma Uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of Uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma Uridine concentration can be useful in the management of medical disorders that are remedied by administration of Uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.
Osama M. Ashour - One of the best experts on this subject based on the ideXlab platform.
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Effect of 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase, on plasma concentration of Uridine released from 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine: relevance to Uridine rescue in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acycloUridine (PSAU) with 2′,3′,5′-tri-O-acetylUridine (TAU) on the levels of plasma Uridine in mice. PSAU is a new lipophilic and potent inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral Uridine. TAU is a prodrug of Uridine and a far superior source of Uridine than Uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of Uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma Uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma Uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma Uridine concentration could be useful in the management of medical disorders that are remedied by administration of Uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.
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Modulation of plasma Uridine concentration by 5-(phenylselenenyl)acycloUridine, an inhibitor of Uridine phosphorylase: relevance to chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Omar N. Al Safarjalani, Naganna M. Goudgaon, Raymond F Schinazi, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acycloUridine (PSAU) in increasing endogenous plasma Uridine concentration as well as its ability to improve the bioavailability of oral Uridine. PSAU is a new potent and specific inhibitor of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in Uridine catabolism. Methods: Oral PSAU was administered orally to mice alone or with Uridine. The plasma levels of PSAU as well as Uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma Uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with Uridine elevated the concentration of plasma Uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral Uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of Uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg Uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg Uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg Uridine was used. Conclusion: The effectiveness of the PSAU plus Uridine combination in elevating and sustaining high plasma Uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of Uridine.
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5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a Uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetylUridine, a prodrug of Uridine, as modulators of plasma Uridine concentration. Implications for chemotherapy.
Biochemical Pharmacology, 1996Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of Uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for Uridine catabolism, and 2',3',5'-tri-O-acetylUridine (TAU), a prodrug of Uridine, were used to investigate the possibility of improving the bioavailability of oral Uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma Uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma Uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than Uridine in improving the bioavailability of plasma Uridine. The relative bioavailability of plasma Uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral Uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma Uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with Uridine or TAU further improved the bioavailability of plasma Uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of Uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of Uridine (1320 mg/kg) increased the relative bioavailability of oral Uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma Uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of Uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma Uridine concentration can be useful in the management of medical disorders that are remedied by administration of Uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.
Sebastian A Leidel - One of the best experts on this subject based on the ideXlab platform.
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wobble Uridine modifications a reason to live a reason to die
RNA Biology, 2017Co-Authors: Raffael Schaffrath, Sebastian A LeidelAbstract:Wobble Uridines (U34) are generally modified in all species. U34 modifications can be essential in metazoans but are not required for viability in fungi. In this review, we provide an overview on the types of modifications and how they affect the physico-chemical properties of wobble Uridines. We describe the molecular machinery required to introduce these modifications into tRNA posttranscriptionally and discuss how posttranslational regulation may affect the activity of the modifying enzymes. We highlight the activity of anticodon specific RNases that target U34 containing tRNA. Finally, we discuss how defects in wobble Uridine modifications lead to phenotypes in different species. Importantly, this review will mainly focus on the cytoplasmic tRNAs of eukaryotes. A recent review has extensively covered their bacterial and mitochondrial counterparts. 1.
