The Experts below are selected from a list of 402 Experts worldwide ranked by ideXlab platform
Long H Dang - One of the best experts on this subject based on the ideXlab platform.
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imaging bacterial infections with radiolabeled 1 2 deoxy 2 fluoro β d arabinofuranosyl 5 iodouracil
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Chetan Bettegowda, Catherine A Foss, Ian Cheong, Yuchuan Wang, Luis A Diaz, Nishant Agrawal, James Fox, James R Dick, Long H DangAbstract:Bacterial infections provide diagnostic dilemmas that could be enlightened by modern imaging technologies. We have developed a simple method for imaging bacterial infections in mice that relies on the phosphorylation and trapping of the thymidine kinase (TK) substrate 1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)-5-[125I] iodouracil ([125I]FIAU) within bacteria. FIAU was found to inhibit the growth of WT Escherichia coli but not a TK– strain, indicating that WT E. coli could metabolize this compound. In silico analyses demonstrated that all pathogenic strains of bacteria whose genomes have been sequenced contain a TK gene highly homologous to the E. coli TK. Accordingly, we demonstrated that localized infections caused by representatives of five genera of bacteria could be readily imaged with [125I]FIAU. Such imaging provides a general method for the diagnosis of localized bacterial infections that could be translatable to the clinic.
Zhang Guo-liang - One of the best experts on this subject based on the ideXlab platform.
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Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1) using human recombinant enzymes and rat liver microsomes in vitro
XENOBIOTICA, 2017Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Lou Ya-qing, Lu Chuang, Cheng Hai-xu, Li Jun, Zhang Guo-liangAbstract:1.The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) in rat and human in vitro. 2.The parent drug of W-1 was incubated with rat liver microsomes (RLMs) or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5, respectively) in the presence or absence of nicotinamide adeninedinucleotide phosphate (NADPH)-regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). 3.The parent drug of W-1 was metabolized in a NADPH-dependent manner in RLMs. The kinetic parameters of prototype W-1 including K-m, V-max, and CLint were 2.3M, 3.3nmol/min/mg protein, and 1.4mL/min/mg protein, respectively. Two metabolites M1 and M2 were observed in shorter retention times (2.988 and 3.188min) with a higher molecular ion at m/z 463.0160 (both M1 and M2) than that of the W-1 parent drug (6.158min with m/z 447.0218). The CYP selective inhibition and recombinant enzymes also showed that two hydroxyl metabolites M1 and M2 are mainly mediated by CYP2C19 and CYP3A4. 4.The identification of CYPs involved in W-1 biotransformation is important to understand and minimize, if possible, the potential of drug-drug interactions.National Natural Science foundation of China [91029747, 81330074, 81473276]SCI(E)ARTICLE8667-6724
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Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats
ARCHIVES OF PHARMACAL RESEARCH, 2016Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Lou Ya-qing, Lu Chuang, Dai Wen-bing, Zhang Qiang, Zhang Guo-liangAbstract:The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C (max)) were 0.42, 1.50 and 2.55 mu g/mL, the area under the curve (AUC(0-t)) were 0.89, 2.27 and 3.96 A mu g/h mL and the plasma half-life (t (1/2)) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.National Natural Science foundation of China [91029747, 81330074, 81473276]; National Basic Research Program of China [2015CB932100]SCI(E)ARTICLEZhangGL168@bjmu.edu.cn7970-9773
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Development and validation of a high performance liquid chromatography method for determination of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor and its application to a pharmacokinetic stud
BIOMEDICAL CHROMATOGRAPHY, 2015Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Ren Hong, Lou Ya-qing, Lu Chuang, Zhang Guo-liangAbstract:A sensitive and selective high-performance liquid chromatographic (HPLC) method for determination of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor in rat plasma, was developed and validated. Chromatographic separation of W-1 and megestrol acetate (internal standard) was achieved on a reversed-phase C-18 column at 25 degrees C. The mobile phase was consisted of acetonitrile-water (60:40, v/v) and pumped at a flow rate of 1.0 mL/min. The ultraviolet (UV) detector was set at the absorption wavelength of 284 nm. The calibration curve for W-1 was linear over the concentration range of 0.01-8 mu g/mL and the lower limit of quantification was 10 ng/mL. The intra- and inter-day precision and accuracy were <8.9 and 5.3%, respectively. The extraction recoveries ranged from 97.9 to 101.6%. The validated HPLC method was successfully applied to a pharmacokinetic study of W-1 in rats. Copyright (c) 2015 John Wiley & Sons, Ltd.National Natural Science foundation of China [91029747, 81330074, 81473276]SCI(E)ARTICLEZhangGL168@bjmu.edu.cn101548-15522
John A Secrist - One of the best experts on this subject based on the ideXlab platform.
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activities of certain 5 substituted 4 thiopyrimidine nucleosides against orthopoxvirus infections
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Earl R Kern, Mark N Prichard, Debra C Quenelle, Kathy A Keith, Kamal N Tiwari, Joseph A Maddry, John A SecristAbstract:As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-Iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log 10 units and about 2 log 10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.
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Activities of Certain 5-Substituted 4′-Thiopyrimidine Nucleosides against Orthopoxvirus Infections
Antimicrobial agents and chemotherapy, 2008Co-Authors: Earl R Kern, Mark N Prichard, Debra C Quenelle, Kathy A Keith, Kamal N Tiwari, Joseph A Maddry, John A SecristAbstract:As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-Iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log 10 units and about 2 log 10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.
Lu Ying-yuan - One of the best experts on this subject based on the ideXlab platform.
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Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1) using human recombinant enzymes and rat liver microsomes in vitro
XENOBIOTICA, 2017Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Lou Ya-qing, Lu Chuang, Cheng Hai-xu, Li Jun, Zhang Guo-liangAbstract:1.The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) in rat and human in vitro. 2.The parent drug of W-1 was incubated with rat liver microsomes (RLMs) or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5, respectively) in the presence or absence of nicotinamide adeninedinucleotide phosphate (NADPH)-regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). 3.The parent drug of W-1 was metabolized in a NADPH-dependent manner in RLMs. The kinetic parameters of prototype W-1 including K-m, V-max, and CLint were 2.3M, 3.3nmol/min/mg protein, and 1.4mL/min/mg protein, respectively. Two metabolites M1 and M2 were observed in shorter retention times (2.988 and 3.188min) with a higher molecular ion at m/z 463.0160 (both M1 and M2) than that of the W-1 parent drug (6.158min with m/z 447.0218). The CYP selective inhibition and recombinant enzymes also showed that two hydroxyl metabolites M1 and M2 are mainly mediated by CYP2C19 and CYP3A4. 4.The identification of CYPs involved in W-1 biotransformation is important to understand and minimize, if possible, the potential of drug-drug interactions.National Natural Science foundation of China [91029747, 81330074, 81473276]SCI(E)ARTICLE8667-6724
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Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats
ARCHIVES OF PHARMACAL RESEARCH, 2016Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Lou Ya-qing, Lu Chuang, Dai Wen-bing, Zhang Qiang, Zhang Guo-liangAbstract:The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C (max)) were 0.42, 1.50 and 2.55 mu g/mL, the area under the curve (AUC(0-t)) were 0.89, 2.27 and 3.96 A mu g/h mL and the plasma half-life (t (1/2)) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.National Natural Science foundation of China [91029747, 81330074, 81473276]; National Basic Research Program of China [2015CB932100]SCI(E)ARTICLEZhangGL168@bjmu.edu.cn7970-9773
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Development and validation of a high performance liquid chromatography method for determination of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor and its application to a pharmacokinetic stud
BIOMEDICAL CHROMATOGRAPHY, 2015Co-Authors: Lu Ying-yuan, Wang Xin, Wang Xiao-wei, Liu Jun-yi, Ren Hong, Lou Ya-qing, Lu Chuang, Zhang Guo-liangAbstract:A sensitive and selective high-performance liquid chromatographic (HPLC) method for determination of 6-benzyl-1-benzyloxymethyl-5-Iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor in rat plasma, was developed and validated. Chromatographic separation of W-1 and megestrol acetate (internal standard) was achieved on a reversed-phase C-18 column at 25 degrees C. The mobile phase was consisted of acetonitrile-water (60:40, v/v) and pumped at a flow rate of 1.0 mL/min. The ultraviolet (UV) detector was set at the absorption wavelength of 284 nm. The calibration curve for W-1 was linear over the concentration range of 0.01-8 mu g/mL and the lower limit of quantification was 10 ng/mL. The intra- and inter-day precision and accuracy were <8.9 and 5.3%, respectively. The extraction recoveries ranged from 97.9 to 101.6%. The validated HPLC method was successfully applied to a pharmacokinetic study of W-1 in rats. Copyright (c) 2015 John Wiley & Sons, Ltd.National Natural Science foundation of China [91029747, 81330074, 81473276]SCI(E)ARTICLEZhangGL168@bjmu.edu.cn101548-15522
Earl R Kern - One of the best experts on this subject based on the ideXlab platform.
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activities of certain 5 substituted 4 thiopyrimidine nucleosides against orthopoxvirus infections
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Earl R Kern, Mark N Prichard, Debra C Quenelle, Kathy A Keith, Kamal N Tiwari, Joseph A Maddry, John A SecristAbstract:As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-Iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log 10 units and about 2 log 10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.
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Activities of Certain 5-Substituted 4′-Thiopyrimidine Nucleosides against Orthopoxvirus Infections
Antimicrobial agents and chemotherapy, 2008Co-Authors: Earl R Kern, Mark N Prichard, Debra C Quenelle, Kathy A Keith, Kamal N Tiwari, Joseph A Maddry, John A SecristAbstract:As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-Iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log 10 units and about 2 log 10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.
