The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Christa L. Brosseau - One of the best experts on this subject based on the ideXlab platform.
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Electrochemical-Surface Enhanced Raman Spectroscopic (EC-SERS) Study of 6-Thiouric Acid: A Metabolite of the Chemotherapy Drug Azathioprine
The Journal of Physical Chemistry C, 2017Co-Authors: B. H. C. Greene, D. S. Alhatab, Cory C. Pye, Christa L. BrosseauAbstract:6-Thiouric Acid (6-TUA) has the potential to be an important biomarker for the action of 6-mercaptopurine (6-MP), an immunosuppressive drug used in patients suffering from acute lymphoblastic leukemia (ALL). 6-TUA, a nonactive metabolite of 6-MP, is excreted in the urine, and routine monitoring of this metabolite can be useful in assessing the efficacy of 6-MP for immune system suppression in patients who have undergone stem cell replacement. In this work, electrochemical surface-enhanced Raman spectroscopy (EC-SERS) is used for the first time to study the adsorption and electrochemical behavior of 6-TUA at a nanostructured silver electrode surface, in both 0.1 M NaF and synthetic urine as supporting electrolytes. In addition, ab initio calculations were completed in an effort to understand the adsorption behavior. It was found that EC-SERS provided excellent signal for 6-TUA down to μM concentrations in synthetic urine and highlights the future potential of EC-SERS for rapid detection of important urine ...
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Electrochemical-Surface Enhanced Raman Spectroscopic (EC-SERS) Study of 6‑Thiouric Acid: A Metabolite of the Chemotherapy Drug Azathioprine
2017Co-Authors: H. C. B. Greene, D. S. Alhatab, Cory C. Pye, Christa L. BrosseauAbstract:6-Thiouric Acid (6-TUA) has the potential to be an important biomarker for the action of 6-mercaptopurine (6-MP), an immunosuppressive drug used in patients suffering from acute lymphoblastic leukemia (ALL). 6-TUA, a nonactive metabolite of 6-MP, is excreted in the urine, and routine monitoring of this metabolite can be useful in assessing the efficacy of 6-MP for immune system suppression in patients who have undergone stem cell replacement. In this work, electrochemical surface-enhanced Raman spectroscopy (EC-SERS) is used for the first time to study the adsorption and electrochemical behavior of 6-TUA at a nanostructured silver electrode surface, in both 0.1 M NaF and synthetic urine as supporting electrolytes. In addition, ab initio calculations were completed in an effort to understand the adsorption behavior. It was found that EC-SERS provided excellent signal for 6-TUA down to μM concentrations in synthetic urine and highlights the future potential of EC-SERS for rapid detection of important urine biomarkers at the patient point-of-care
J. S. Cameron - One of the best experts on this subject based on the ideXlab platform.
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the importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients
Transplantation, 1992Co-Authors: P R Chocair, Jacqueline A. Duley, H. A. Simmonds, J. S. CameronAbstract:The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-Thiouric Acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites.
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Thiopurine Methyltransferase Activity and Efficacy of Azathioprine Immunosuppression in Transplant Recipients
Advances in experimental medicine and biology, 1991Co-Authors: P R Chocair, H. A. Simmonds, John A. Duley, J. S. CameronAbstract:Azathioprine (AZA) has been given to transplanted patients since 1963 (1), but despite extensive use its metabolism is still not completely understood. After oral administration, it is converted rapidly to 6-mercaptopurine (6MP), mainly in the liver and the gut (2). 6MP is metabolised by three competing pathways (Figure 1): A) conversion to 6-thioinosinic Acid by hypoxanthine guanine phosphoribosyltransferase (HPRT) and thence thioguanine nucleotides which exert their cytotoxicity by incorporation into DNA and RNA (2,3); B) catabolism by xanthine oxidase (XOD) to 6-Thiouric Acid; C) conversion to 6-methyl mercaptopurine (6MeMP) by the enzyme thiopurine methyl transferase (TPMT), which has a wide range of activity in the normal population and is inherited in a autosomal codominant fashion (3,4).
P R Chocair - One of the best experts on this subject based on the ideXlab platform.
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the importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients
Transplantation, 1992Co-Authors: P R Chocair, Jacqueline A. Duley, H. A. Simmonds, J. S. CameronAbstract:The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-Thiouric Acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites.
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Thiopurine Methyltransferase Activity and Efficacy of Azathioprine Immunosuppression in Transplant Recipients
Advances in experimental medicine and biology, 1991Co-Authors: P R Chocair, H. A. Simmonds, John A. Duley, J. S. CameronAbstract:Azathioprine (AZA) has been given to transplanted patients since 1963 (1), but despite extensive use its metabolism is still not completely understood. After oral administration, it is converted rapidly to 6-mercaptopurine (6MP), mainly in the liver and the gut (2). 6MP is metabolised by three competing pathways (Figure 1): A) conversion to 6-thioinosinic Acid by hypoxanthine guanine phosphoribosyltransferase (HPRT) and thence thioguanine nucleotides which exert their cytotoxicity by incorporation into DNA and RNA (2,3); B) catabolism by xanthine oxidase (XOD) to 6-Thiouric Acid; C) conversion to 6-methyl mercaptopurine (6MeMP) by the enzyme thiopurine methyl transferase (TPMT), which has a wide range of activity in the normal population and is inherited in a autosomal codominant fashion (3,4).
B. H. C. Greene - One of the best experts on this subject based on the ideXlab platform.
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Electrochemical-Surface Enhanced Raman Spectroscopic (EC-SERS) Study of 6-Thiouric Acid: A Metabolite of the Chemotherapy Drug Azathioprine
The Journal of Physical Chemistry C, 2017Co-Authors: B. H. C. Greene, D. S. Alhatab, Cory C. Pye, Christa L. BrosseauAbstract:6-Thiouric Acid (6-TUA) has the potential to be an important biomarker for the action of 6-mercaptopurine (6-MP), an immunosuppressive drug used in patients suffering from acute lymphoblastic leukemia (ALL). 6-TUA, a nonactive metabolite of 6-MP, is excreted in the urine, and routine monitoring of this metabolite can be useful in assessing the efficacy of 6-MP for immune system suppression in patients who have undergone stem cell replacement. In this work, electrochemical surface-enhanced Raman spectroscopy (EC-SERS) is used for the first time to study the adsorption and electrochemical behavior of 6-TUA at a nanostructured silver electrode surface, in both 0.1 M NaF and synthetic urine as supporting electrolytes. In addition, ab initio calculations were completed in an effort to understand the adsorption behavior. It was found that EC-SERS provided excellent signal for 6-TUA down to μM concentrations in synthetic urine and highlights the future potential of EC-SERS for rapid detection of important urine ...
P. M. Hooymans - One of the best experts on this subject based on the ideXlab platform.
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The role of xanthine oxidase in thiopurine metabolism: a case report.
Therapeutic drug monitoring, 2007Co-Authors: Dennis R Wong, Luc J J Derijks, Meyno O Den Dulk, Edy H K M Gemmeke, P. M. HooymansAbstract:Azathioprine (AZA) is widely used in the treatment of autoimmune inflammatory diseases. AZA is normally rapidly and almost completely converted to 6-mercaptopurine (6-MP) in the liver, which is further metabolized into a variety of pharmacologic active thiopurine metabolites. 6-MP is catabolized by xanthine oxidase (XO) to the inactive metabolite 6-Thiouric Acid. The authors report the case of a woman with chronic autoimmune pancreatitis unable to form active thiopurine metabolites. The 55-year-old woman presented with weight loss, progressive elevation of liver transaminases, and serum amylase. She was treated with prednisolone 30 mg/day (1 mg/kg) and AZA was increased to 75 mg/day (2.5 mg/kg); this was later increased to 150 mg/day (5 mg/kg). Despite good patient compliance, the active metabolites of AZA, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine ribonucleotides (6-MMPR) could not be detected in the erythrocytes (RBC). Subsequently, AZA was switched to high-dose 6-MP (2.5 mg/kg) and the XO inhibitor allopurinol was added. After 1 week, this combination led to a high 6-TGN level of 616 pmol/8 x 10(8) RBC and a 6-MMPR level of 1319 pmol/8 x 10(8) RBC. Three weeks after starting treatment, 6-TGN and 6-MMPR even reached toxic levels (1163 pmol/8 x 10(8) RBC and 10015 pmol/8 x 10(8) RBC, respectively) so that 6-MP treatment was discontinued. To elucidate this finding, 6-MP (1.7 mg/kg) was prescribed for 3 days without allopurinol. The woman was not able to form active thiopurine metabolites. According to the authors, this is the first report of a patient unable to form detectable active thiopurine metabolites on AZA and 6-MP therapy despite good patient compliance. High XO activity led to an inability to form detectable levels of active thiopurine metabolites 6-TGN and 6-MMPR. This finding emphasizes the important role of XO in the biotransformation of thiopurines.
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Non‐detectable levels of 6‐thioguanine nucleotides and 6‐methylmercaptopurine in a patient treated with azathioprine: a case report
British Journal of Clinical Pharmacology, 2007Co-Authors: Dennis R Wong, Luc J J Derijks, Meyno O Den Dulk, Edy H K M Gemmeke, P. M. HooymansAbstract:Introduction: Azathioprine (AZA) is a thiopurine prodrug clinically used for immunosuppression in the treatment of auto-immune inflammatory diseases and in regimens of organ transplantations. The pharmacological action of AZA is based on the formation of 6-mercaptopurine (6-MP), which is metabolised into a variety of active thiopurine-nucleotide metabolites. We report the case of a 55 year old woman (bodyweight 30 kg) with chronic pancreatitis, weight loss, and progressive elevation of liver transaminases and serum amylase. Case description: The woman was treated with prednisolone (30 mg 1 dd; tapered 5 mg each week) and AZA (75 mg 1 dd; 5 weeks later 150 mg 1 dd). Despite good patient-compliance verified during hospital-stay, none of the active metabolites of AZA, 6-thioguanine-nucleotides (6TGN) and 6-methylmercaptopurine ribonucleotides (6MMPR), were detected in erythrocytes. After two months of treatment clinical improvement was achieved, but no normalisation of laboratory parameters. Subsequently, AZA was switched to 6-MP 75 mg 1 dd, and allopurinol 100 mg 1 dd was added. After one week the 6TGN level was 616 pmol/ 8 × 108 red blood cells (RBC), the 6MMPR level was 1319 pmol/ 8 × 108 RBC. Two weeks later the 6TGN level was 1163 pmol/ 8 × 108 RBC and the 6MMPR level 10015 pmol/ 8 × 108 RBC. These 6TGN and 6MMPR levels were higher than the upper limits of the therapeutic ranges (500 pmol/ 8 × 108 RBC and 5700 pmol/ 8 × 108 RBC, respectively). Therefore, treatment with 6-MP was discontinued. A week later the 6TGN and 6MMPR levels decreased to 686 pmol/ 8 × 108 RBC and 4027 pmol/ 8 × 108 RBC, respectively. Genotyping of the enzym thiopurine S-methyl transferase (TPMT) revealed a wild-type TPMT (*1/*1) genotype. Discussion: To our knowledge this is the first report of a patient who was not able to form detectable active thiopurine metabolites on the treatment with AZA. AZA is normally rapidly and almost completely converted to 6-MP and methylnitroimidazole in the liver. 6-MP is then further catabolised by xanthine-oxidase (XO) and TPMT or anabolised by hypoxanthine phosphoribosyl transferase (HPRT). Remarkably, treatment with 6-MP in combination with the XO-inhibitor allopurinol resulted in a myelotoxic 6TGN level in the first week after start of treatment. There are two hypotheses on the mechanism by which this finding could be explained. First, an ‘ultra-high’ XO activity results in a direct and complete conversion of 6-MP into 6-Thiouric Acid. Secondly, AZA is not converted into 6-MP. Consequently, there is no formation of active thiopurine nucleotides out of 6-MP. Also, a combination of these two mechanisms could lead to a decreased formation of active thiopurine metabolites. Conclusion: Our finding indicates non-conventional insights in the biotransformation of AZA contributing to an interindividual variation in thiopurine metabolism.
