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Graeme Eisenhofer - One of the best experts on this subject based on the ideXlab platform.
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age specific pediatric reference intervals for plasma free normetanephrine metanephrine 3 methoxytyramine and 3 o methyldopa particular importance for early infancy
Clinica Chimica Acta, 2019Co-Authors: Mirko Peitzsch, Anastasios Mangelis, Graeme Eisenhofer, Angela HuebnerAbstract:Abstract Background Availability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. Methods Plasma concentrations of 3-Methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. Results Concentrations of plasma free normetanephrine, 3-Methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were Conclusion The dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-Methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.
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update on modern management of pheochromocytoma and paraganglioma
Endocrinology and Metabolism, 2017Co-Authors: Jacques W M Lenders, Graeme EisenhoferAbstract:Despite all technical progress in modern diagnostic methods and treatment modalities of pheochromocytoma/paraganglioma, early consideration of the presence of these tumors remains the pivotal link towards the best possible outcome for patients. A timely diagnosis and proper treatment can prevent the wide variety of potentially catastrophic cardiovascular complications. Modern biochemical testing should include tests that offer the best available diagnostic performance, measurements of metanephrines and 3-Methoxytyramine in plasma or urine. To minimize false-positive test results particular attention should be paid to pre-analytical sampling conditions. In addition to anatomical imaging by computed tomography (CT) or magnetic resonance imaging, new promising functional imaging modalities of photon emission tomography/CT using with somatostatin analogues such as ⁶⁸Ga-DOTATATE (⁶⁸Ga-labeled DOTA(0)-Tyr(3)-octreotide) will probably replace ¹²³I-MIBG (iodine-123-metaiodobenzylguanidine) in the near future. As nearly half of all pheochromocytoma patients harbor a mutation in one of the 14 tumor susceptibility genes, genetic testing and counseling should at least be considered in all patients with a proven tumor. Post-surgical annual follow-up of patients by measurements of plasma or urinary metanephrines should last for at least 10 years for timely detection of recurrent or metastatic disease. Patients with a high risk for recurrence or metastatic disease (paraganglioma, young age, multiple or large tumors, genetic background) should be followed up lifelong.
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interference from 3 o methyldopa with ultra high performance lc ms ms measurements of plasma metanephrines chromatographic separation remains important
Clinical Chemistry, 2015Co-Authors: Mirko Peitzsch, Joanne Adaway, Graeme EisenhoferAbstract:To the Editor: Wright et al. (1) recently described the use of multiple reaction monitoring with multistage fragmentation (MRM3), for which the conventional product ion produced by collision-induced fragmentation of the precursor ion [M+H+] is further fragmented in an ion trap to produce a “second generation product ion.” This approach can eliminate occasional interferences during measurements of metanephrines from unknown substances in plasma samples. We outline here interference from an endogenous analyte present in all plasma samples, 3- O -methyldopa, which cannot be eliminated by MRM3. The interference affects measurements of methoxytyramine, the O -methylated metabolite of dopamine, important for diagnosis of chromaffin cell tumors and identification of metastatic disease (2, 3). 3- O -Methyldopa is formed by the action of catechol- O -methyltransferase (COMT) on l-dopa, the immediate precursor of dopamine. 3- O -methyldopa is present in plasma at 50–300 nmol/L (10–63 ng/mL) concentrations (4), more than 10-fold higher than l-dopa, reflecting slow renal clearance. In contrast, concentrations of methoxytyramine normally do not exceed 0.11 nmol/L (18 pg/mL), with cutoffs of 0.20–0.41 nmol/L (33–69 pg/mL) described for diagnosis of metastatic disease (3). Suspicion that 3- …
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laboratory evaluation of pheochromocytoma and paraganglioma
Clinical Chemistry, 2014Co-Authors: Graeme Eisenhofer, Mirko PeitzschAbstract:BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are potentially lethal yet usually surgically curable causes of endocrine hypertension; therefore, once clinical suspicion is aroused it is imperative that clinicians choose the most appropriate laboratory tests to identify the tumors. CONTENT: Compelling evidence now indicates that initial screening for PPGLs should include measurements of plasma free metanephrines or urine fractionated metanephrines. LC-MS/MS offers numerous advantages over other analytical methods and is the method of choice when measurements include methoxytyramine, the O -methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimum diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 min of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly collected blood samples during screening, together with use of age-adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal vs extraadrenal locations of tumors, as well as presence of metastases and underlying germline mutations of tumor susceptibility genes. SUMMARY: Carried out correctly at specialist endocrine centers, collection of blood for measurements of plasma normetanephrine, metanephrine, and methoxytyramine not only provides high accuracy for diagnosis of PPGLs, but can also guide clinical decision-making about follow-up imaging strategies, genetic testing, and therapeutic options. At other centers, measurements of urine fractionated metanephrines will identify most PPGLs.
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analysis of plasma 3 methoxytyramine normetanephrine and metanephrine by ultraperformance liquid chromatography tandem mass spectrometry utility for diagnosis of dopamine producing metastatic phaeochromocytoma
Annals of Clinical Biochemistry, 2013Co-Authors: Mirko Peitzsch, Aleksander Prejbisz, Felix Beuschlein, Matthias Krois, Wiebke Arlt, Andrzej Januszewicz, Gabriele Siegert, Graeme EisenhoferAbstract:BackgroundMeasurements of plasma normetanephrine (NMN) and metanephrine (MN) provide a sensitive test for diagnosis of phaeochromocytomas and paragangliomas (PPGLs), but do not allow detection of dopamine-producing tumours. Here we introduce a novel mass spectrometric based method coupled to ultraperformance liquid chromatography (LC-MS/MS) for measuring NMN, MN and 3-Methoxytyramine (MTY), the O-methylated metabolite of dopamine.MethodsSpecific collision-induced fragment ions assessed by multireaction monitoring transitions were used for identification, with quantification according to signal intensities of analytes relative to stable isotope labelled internal standards. Results for solid-phase extracted samples from 196 subjects analysed by LC-MS/MS were compared with those analysed by liquid chromatography with electrochemical detection (LC-ECD). Concentration ranges in 125 volunteers were compared with those from 63 patients with PPGLs, including 14 with metastatic disease.ResultsThe LC-MS/MS method s...
Mirko Peitzsch - One of the best experts on this subject based on the ideXlab platform.
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biochemical testing for neuroblastoma using plasma free 3 o methyldopa 3 methoxytyramine and normetanephrine
Pediatric Blood & Cancer, 2020Co-Authors: Mirko Peitzsch, Elizabeth R Butch, Elizabeth Lovorn, Anastasios Mangelis, Wayne L Furman, Victor M Santana, Barbara Hero, Frank Berthold, Barry L Shulkin, Angela HuebnerAbstract:BACKGROUND Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA. PROCEDURE Plasma concentrations of 3-Methoxytyramine, normetanephrine, and metanephrine were measured in two pediatric cohorts: (i) 96 children with confirmed neuroblastoma and (ii) 41 children with signs and symptoms of a catecholamine-producing tumor or other neoplasms and in whom neuroblastoma was excluded. Additional measurements of plasma 3-O-methyldopa and relationships of metabolites to MYCN amplification were examined in patient subgroups. RESULTS Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-Methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P < 0.0001) than that of 82.2% for HVA and VMA. One of the two patients with normal plasma results showed an elevation of plasma 3-O-methyldopa. Diagnostic specificities were, respectively, 95.1% and 84.8%. Areas under receiver-operating characteristic curves confirmed the superior diagnostic power of the plasma than the urinary test (0.994 vs 0.945; P = 0.0095). Ratios of plasma 3-Methoxytyramine to normetanephrine were 7.2-fold higher (P < 0.0001) for patients who had neuroblastomas with MYCN amplification than without MYCN amplification. CONCLUSIONS Measurements of plasma 3-Methoxytyramine and normetanephrine provide a highly accurate diagnostic test for neuroblastoma and also offer potential for prognostic risk stratification.
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age specific pediatric reference intervals for plasma free normetanephrine metanephrine 3 methoxytyramine and 3 o methyldopa particular importance for early infancy
Clinica Chimica Acta, 2019Co-Authors: Mirko Peitzsch, Anastasios Mangelis, Graeme Eisenhofer, Angela HuebnerAbstract:Abstract Background Availability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. Methods Plasma concentrations of 3-Methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. Results Concentrations of plasma free normetanephrine, 3-Methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were Conclusion The dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-Methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.
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interference from 3 o methyldopa with ultra high performance lc ms ms measurements of plasma metanephrines chromatographic separation remains important
Clinical Chemistry, 2015Co-Authors: Mirko Peitzsch, Joanne Adaway, Graeme EisenhoferAbstract:To the Editor: Wright et al. (1) recently described the use of multiple reaction monitoring with multistage fragmentation (MRM3), for which the conventional product ion produced by collision-induced fragmentation of the precursor ion [M+H+] is further fragmented in an ion trap to produce a “second generation product ion.” This approach can eliminate occasional interferences during measurements of metanephrines from unknown substances in plasma samples. We outline here interference from an endogenous analyte present in all plasma samples, 3- O -methyldopa, which cannot be eliminated by MRM3. The interference affects measurements of methoxytyramine, the O -methylated metabolite of dopamine, important for diagnosis of chromaffin cell tumors and identification of metastatic disease (2, 3). 3- O -Methyldopa is formed by the action of catechol- O -methyltransferase (COMT) on l-dopa, the immediate precursor of dopamine. 3- O -methyldopa is present in plasma at 50–300 nmol/L (10–63 ng/mL) concentrations (4), more than 10-fold higher than l-dopa, reflecting slow renal clearance. In contrast, concentrations of methoxytyramine normally do not exceed 0.11 nmol/L (18 pg/mL), with cutoffs of 0.20–0.41 nmol/L (33–69 pg/mL) described for diagnosis of metastatic disease (3). Suspicion that 3- …
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laboratory evaluation of pheochromocytoma and paraganglioma
Clinical Chemistry, 2014Co-Authors: Graeme Eisenhofer, Mirko PeitzschAbstract:BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are potentially lethal yet usually surgically curable causes of endocrine hypertension; therefore, once clinical suspicion is aroused it is imperative that clinicians choose the most appropriate laboratory tests to identify the tumors. CONTENT: Compelling evidence now indicates that initial screening for PPGLs should include measurements of plasma free metanephrines or urine fractionated metanephrines. LC-MS/MS offers numerous advantages over other analytical methods and is the method of choice when measurements include methoxytyramine, the O -methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimum diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 min of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly collected blood samples during screening, together with use of age-adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal vs extraadrenal locations of tumors, as well as presence of metastases and underlying germline mutations of tumor susceptibility genes. SUMMARY: Carried out correctly at specialist endocrine centers, collection of blood for measurements of plasma normetanephrine, metanephrine, and methoxytyramine not only provides high accuracy for diagnosis of PPGLs, but can also guide clinical decision-making about follow-up imaging strategies, genetic testing, and therapeutic options. At other centers, measurements of urine fractionated metanephrines will identify most PPGLs.
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biochemical diagnosis of phaeochromocytoma using plasma free normetanephrine metanephrine and methoxytyramine importance of supine sampling under fasting conditions
Clinical Endocrinology, 2014Co-Authors: Roland Därr, Mirko Peitzsch, Christina Pamporaki, Konstanze Miehle, Aleksander Prejbisz, Mariola Peczkowska, Dirk Weismann, Felix Beuschlein, Richard O Sinnott, Stefan R BornsteinAbstract:SummaryObjective To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. Design and methods Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant). Results Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97·5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1·29 vs 0·79 nmol/l), metanephrine (0·49 vs 0·41 nmol/l) and methoxytyramine (0·42 vs 0·18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%). Conclusions High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5·7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions.
Maki Okada - One of the best experts on this subject based on the ideXlab platform.
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microdialysis with radiometric monitoring of l β 11c dopa to assess dopaminergic metabolism effect of inhibitors of l amino acid decarboxylase monoamine oxidase and catechol o methyltransferase on rat striatal dialysate
Journal of Cerebral Blood Flow and Metabolism, 2011Co-Authors: Maki Okada, Ryuji Nakao, Rie Hosoi, Mingrong Zhang, Toshimitsu Fukumura, Kazutoshi Suzuki, Osamu InoueAbstract:The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy--phenylalanine (-DOPA) by aromatic -amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor -[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of -[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of -[β-11C]DOPA and -3-O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT inhibitors increased the production of [11C]3-Methoxytyramine and [11C]DOPAC, respectively. These results reflect the -DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.
Elena Cichero - One of the best experts on this subject based on the ideXlab platform.
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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study.
Journal of Medicinal Chemistry, 2016Co-Authors: Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena CicheroAbstract:The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-Methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1–16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2...
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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study
2016Co-Authors: Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena CicheroAbstract:The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-Methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1–16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models
Waqas Nawaz - One of the best experts on this subject based on the ideXlab platform.
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the emerging roles of human trace amines and human trace amine associated receptors htaars in central nervous system
Biomedicine & Pharmacotherapy, 2016Co-Authors: Muhammad Zahid Khan, Waqas NawazAbstract:Human trace amines (TAs) are endogenous compounds, previously almost ignored in human pathology for many reasons (difficulty of their measurement in biological fluids, unknown receptors for elusive amines), are now considered to play a significant role in synaptic transmission within the central nervous system (CNS) acting as neuromodulators. The recent discovery of a novel family of G-protein-coupled receptors (GPCRs) that includes individual members that are highly specific for TAs indicates a potential role for TAs as vertebrate neurotransmitters or neuromodulators, although the majority of these GPCRs so far have not been demonstrated to be activated by TAs. Human trace amine receptors (including TAAR1 TAAR2 TAAR5 TAAR6 TAAR8 TAAR9) are expressed in the brain and play significant physiological and neuropathological roles by activation of trace amines. We herein discuss the recent findings that provide insights into the functional roles of human trace amines (including P-Octopamine, β phenylethylamine, Tryptamine, Tyramine, Synephrine, 3-Iodothyronamine, 3-Methoxytyramine, N-Methyltyramine, N-Methylphenethylamine) in brain. Furthermore, we discuss the known functions of human trace amine receptors in brain.
