{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:39:34Z","timestamp":1784623174669,"version":"3.55.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Theravance Biopharma R&D, Inc."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Auton Res"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (<jats:italic>n<\/jats:italic>OH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Patients with <jats:italic>n<\/jats:italic>OH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5\u00a0days in the clinical research unit, followed by 20\u00a0weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Thirty-four patients with <jats:italic>n<\/jats:italic>OH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6\u20139\u00a0h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10\u00a0mg once daily. Plasma ampreloxetine concentrations reached steady state by 2\u00a0weeks, with stable plasma levels over 24\u00a0h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005), plasma DHPG significantly declined by 22% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), and the NE:DHPG ratio significantly increased (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with <jats:italic>n<\/jats:italic>OH.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10286-021-00800-x","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:02:41Z","timestamp":1617037361000},"page":"395-403","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7474-1328","authenticated-orcid":false,"given":"Arthur","family":"Lo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Norcliffe-Kaufmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Vickery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bourdet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8621-500X","authenticated-orcid":false,"given":"Jitendra","family":"Kanodia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"800_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1056\/NEJMra1509723","volume":"382","author":"H Kaufmann","year":"2020","unstructured":"Kaufmann H, Norcliffe-Kaufmann L, Palma JA (2020) Baroreflex dysfunction. N Engl J Med 382:163\u2013178. https:\/\/doi.org\/10.1056\/NEJMra1509723","journal-title":"N Engl J Med"},{"key":"800_CR2","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.jtbi.2003.09.014","volume":"226","author":"MR Bennett","year":"2004","unstructured":"Bennett MR, Farnell L, Gibson WG, Blair D (2004) A quantitative description of the diffusion of noradrenaline in the media of blood vessels following its release from sympathetic varicosities. J Theor Biol 226:359\u2013372. https:\/\/doi.org\/10.1016\/j.jtbi.2003.09.014","journal-title":"J Theor Biol"},{"key":"800_CR3","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/(SICI)1097-0029(19980915)42:6<433::AID-JEMT6>3.0.CO;2-N","volume":"42","author":"MR Bennett","year":"1998","unstructured":"Bennett MR, Cheung A, Brain KL (1998) Sympathetic neuromuscular transmission at a varicosity in a syncytium. Microsc Res Tech 42:433\u2013450. https:\/\/doi.org\/10.1002\/(SICI)1097-0029(19980915)42:6%3c433::AID-JEMT6%3e3.0.CO;2-N","journal-title":"Microsc Res Tech"},{"key":"800_CR4","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1113\/jphysiol.1974.sp010556","volume":"239","author":"JB Furness","year":"1974","unstructured":"Furness JB, Marshall JM (1974) Correlation of the directly observed responses of mesenteric vessels of the rat to nerve stimulation and noradrenaline with the distribution of adrenergic nerves. J Physiol 239:75\u201388. https:\/\/doi.org\/10.1113\/jphysiol.1974.sp010556","journal-title":"J Physiol"},{"key":"800_CR5","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s10286-011-0119-5","volume":"21","author":"R Freeman","year":"2011","unstructured":"Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, van Dijk JG (2011) Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 21:69\u201372. https:\/\/doi.org\/10.1007\/s10286-011-0119-5","journal-title":"Clin Auton Res"},{"issue":"Pt 1","key":"800_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1469-7793.1999.0001o.x","volume":"519","author":"AA Smit","year":"1999","unstructured":"Smit AA, Halliwill JR, Low PA, Wieling W (1999) Pathophysiological basis of orthostatic hypotension in autonomic failure. J Physiol 519(Pt 1):1\u201310. https:\/\/doi.org\/10.1111\/j.1469-7793.1999.0001o.x","journal-title":"J Physiol"},{"key":"800_CR7","doi-asserted-by":"publisher","first-page":"6756","DOI":"10.1021\/ac060440u","volume":"78","author":"J Park","year":"2006","unstructured":"Park J, Galligan JJ, Fink GD, Swain GM (2006) In vitro continuous amperometry with a diamond microelectrode coupled with video microscopy for simultaneously monitoring endogenous norepinephrine and its effect on the contractile response of a rat mesenteric artery. Anal Chem 78:6756\u20136764. https:\/\/doi.org\/10.1021\/ac060440u","journal-title":"Anal Chem"},{"key":"800_CR8","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/s0163-7258(01)00144-9","volume":"91","author":"G Eisenhofer","year":"2001","unstructured":"Eisenhofer G (2001) The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 91:35\u201362. https:\/\/doi.org\/10.1016\/s0163-7258(01)00144-9","journal-title":"Pharmacol Ther"},{"key":"800_CR9","doi-asserted-by":"publisher","first-page":"H1273","DOI":"10.1152\/ajpheart.00492.2012","volume":"303","author":"C Schroeder","year":"2012","unstructured":"Schroeder C, Jordan J (2012) Norepinephrine transporter function and human cardiovascular disease. Am J Physiol Heart Circ Physiol 303:H1273-1282. https:\/\/doi.org\/10.1152\/ajpheart.00492.2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"800_CR10","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1056\/NEJM200002243420803","volume":"342","author":"JR Shannon","year":"2000","unstructured":"Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D (2000) Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 342:541\u2013549. https:\/\/doi.org\/10.1056\/NEJM200002243420803","journal-title":"N Engl J Med"},{"key":"800_CR11","volume-title":"Goodman & Gilman\u2019s the pharmacological basis of therapeutics","author":"LL Brunton","year":"2018","unstructured":"Brunton LL, Hilal-Dandan R, Knollmann BC (2018) Goodman & Gilman\u2019s the pharmacological basis of therapeutics, 13th edn. McGraw-Hill Education, New York","edition":"13"},{"key":"800_CR12","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s10571-006-9041-0","volume":"26","author":"DS Goldstein","year":"2006","unstructured":"Goldstein DS, Eisenhofer G, Kopin IJ (2006) Clinical catecholamine neurochemistry: a legacy of Julius Axelrod. Cell Mol Neurobiol 26:695\u2013702. https:\/\/doi.org\/10.1007\/s10571-006-9041-0","journal-title":"Cell Mol Neurobiol"},{"key":"800_CR13","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1093\/clinchem\/32.11.2030","volume":"32","author":"G Eisenhofer","year":"1986","unstructured":"Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL, Kopin IJ (1986) Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem 32:2030\u20132033","journal-title":"Clin Chem"},{"key":"800_CR14","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1042\/cs0800257","volume":"80","author":"G Eisenhofer","year":"1991","unstructured":"Eisenhofer G, Esler MD, Meredith IT, Ferrier C, Lambert G, Jennings G (1991) Neuronal re-uptake of noradrenaline by sympathetic nerves in humans. Clin Sci (Lond) 80:257\u2013263. https:\/\/doi.org\/10.1042\/cs0800257","journal-title":"Clin Sci (Lond)"},{"key":"800_CR15","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1161\/01.cir.85.5.1775","volume":"85","author":"G Eisenhofer","year":"1992","unstructured":"Eisenhofer G, Esler MD, Meredith IT, Dart A, Cannon RO 3rd, Quyyumi AA, Lambert G, Chin J, Jennings GL, Goldstein DS (1992) Sympathetic nervous function in human heart as assessed by cardiac spillovers of dihydroxyphenylglycol and norepinephrine. Circulation 85:1775\u20131785. https:\/\/doi.org\/10.1161\/01.cir.85.5.1775","journal-title":"Circulation"},{"key":"800_CR16","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1172\/JCI113298","volume":"81","author":"DS Goldstein","year":"1988","unstructured":"Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ (1988) Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest 81:213\u2013220. https:\/\/doi.org\/10.1172\/JCI113298","journal-title":"J Clin Invest"},{"key":"800_CR17","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1161\/01.hyp.5.1.100","volume":"5","author":"DS Goldstein","year":"1983","unstructured":"Goldstein DS, Lake CR, Chernow B, Ziegler MG, Coleman MD, Taylor AA, Mitchell JR, Kopin IJ, Keiser HR (1983) Age-dependence of hypertensive-normotensive differences in plasma norepinephrine. Hypertension 5:100\u2013104. https:\/\/doi.org\/10.1161\/01.hyp.5.1.100","journal-title":"Hypertension"},{"key":"800_CR18","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/978-3-7091-9113-2_57","volume":"32","author":"KH Graefe","year":"1990","unstructured":"Graefe KH, Halbrugge T, Gerlich M, Ludwig J (1990) The importance of plasma 3,4-dihydroxyphenylglycol (DOPEG) in analyses of the sympathetic nervous system in vivo. J Neural Transm Suppl 32:421\u2013429. https:\/\/doi.org\/10.1007\/978-3-7091-9113-2_57","journal-title":"J Neural Transm Suppl"},{"key":"800_CR19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1097\/JCP.0000000000000061","volume":"34","author":"JC Chappell","year":"2014","unstructured":"Chappell JC, Eisenhofer G, Owens MJ, Haber H, Lachno DR, Dean RA, Knadler MP, Nemeroff CB, Mitchell MI, Detke MJ, Iyengar S, Pangallo B, Lobo ED (2014) Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects. J Clin Psychopharmacol 34:9\u201316. https:\/\/doi.org\/10.1097\/JCP.0000000000000061","journal-title":"J Clin Psychopharmacol"},{"key":"800_CR20","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1007\/s00415-012-6736-7","volume":"260","author":"M Metzler","year":"2013","unstructured":"Metzler M, Duerr S, Granata R, Krismer F, Robertson D, Wenning GK (2013) Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol 260:2212\u20132219. https:\/\/doi.org\/10.1007\/s00415-012-6736-7","journal-title":"J Neurol"},{"key":"800_CR21","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/mdc3.12478","volume":"4","author":"JA Palma","year":"2017","unstructured":"Palma JA, Kaufmann H (2017) Epidemiology, diagnosis, and management of neurogenic orthostatic hypotension. Mov Disord Clin Pract 4:298\u2013308. https:\/\/doi.org\/10.1002\/mdc3.12478","journal-title":"Mov Disord Clin Pract"},{"key":"800_CR22","first-page":"S1612","volume":"33","author":"SS Hegde","year":"2018","unstructured":"Hegde SS, Pulido-Rios MT, McNamara A, Kanodia J, Martin WJ, Smith JAM, Bourdet DL (2018) Preclinical cardiovascular sympathoexcitatory effects of TD-9855, a novel norepinephrine transporter (NET) inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in patients with primary autonomic failure [abstract #1612]. Mov Disord 33:S1612","journal-title":"Mov Disord"},{"key":"800_CR23","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00918-7","author":"J Kanodia","year":"2020","unstructured":"Kanodia J, Lo A, Baldwin RM, Graham RA, Bourdet DL (2020) Pharmacokinetics of ampreloxetine, a norepinephrine reuptake inhibitor, in healthy subjects and adults with attention-deficit\/hyperactive disorder or fibromyalgia pain. Clin Pharmacokinet. https:\/\/doi.org\/10.1007\/s40262-020-00918-7 (Epub ahead of print)","journal-title":"Clin Pharmacokinet"},{"key":"800_CR24","doi-asserted-by":"publisher","first-page":"pyu27","DOI":"10.1093\/ijnp\/pyu027","volume":"18","author":"JA Smith","year":"2014","unstructured":"Smith JA, Bourdet DL, Daniels OT, Ding YS, Gallezot JD, Henry S, Kim KH, Kshirsagar S, Martin WJ, Obedencio GP, Stangeland E, Tsuruda PR, Williams W, Carson RE, Patil ST (2014) Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. Int J Neuropsychopharmacol 18:pyu27. https:\/\/doi.org\/10.1093\/ijnp\/pyu027","journal-title":"Int J Neuropsychopharmacol"},{"key":"800_CR25","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1161\/HYPERTENSIONAHA.109.136853","volume":"54","author":"EM Garland","year":"2009","unstructured":"Garland EM, Gamboa A, Okamoto L, Raj SR, Black BK, Davis TL, Biaggioni I, Robertson D (2009) Renal impairment of pure autonomic failure. Hypertension 54:1057\u20131061. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.109.136853","journal-title":"Hypertension"},{"key":"800_CR26","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1212\/01.wnl.0000324625.00404.15","volume":"71","author":"S Gilman","year":"2008","unstructured":"Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670\u2013676. https:\/\/doi.org\/10.1212\/01.wnl.0000324625.00404.15","journal-title":"Neurology"},{"key":"800_CR27","doi-asserted-by":"publisher","first-page":"4047392","DOI":"10.1155\/2017\/4047392","volume":"2017","author":"MR Luquin","year":"2017","unstructured":"Luquin MR, Kulisevsky J, Martinez-Martin P, Mir P, Tolosa ES (2017) Consensus on the definition of advanced Parkinson\u2019s disease: a neurologists-based Delphi Study (CEPA study). Parkinsons Dis 2017:4047392. https:\/\/doi.org\/10.1155\/2017\/4047392","journal-title":"Parkinsons Dis"},{"key":"800_CR28","unstructured":"Declaration of Helsinki (1964) Recommendations guiding doctors in clinical research. Helsinki, 18th World Medical Assembly, Finland"},{"key":"800_CR29","doi-asserted-by":"publisher","first-page":"461","DOI":"10.7326\/0003-4819-130-6-199903160-00002","volume":"130","author":"AS Levey","year":"1999","unstructured":"Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461\u2013470. https:\/\/doi.org\/10.7326\/0003-4819-130-6-199903160-00002","journal-title":"Ann Intern Med"},{"key":"800_CR30","doi-asserted-by":"publisher","first-page":"247","DOI":"10.7326\/0003-4819-145-4-200608150-00004","volume":"145","author":"AS Levey","year":"2006","unstructured":"Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F, Chronic Kidney Disease Epidemiology C (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247\u2013254. https:\/\/doi.org\/10.7326\/0003-4819-145-4-200608150-00004","journal-title":"Ann Intern Med"},{"key":"800_CR31","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.parkreldis.2020.04.011","volume":"75","author":"JA Palma","year":"2020","unstructured":"Palma JA, Redel-Traub G, Porciuncula A, Samaniego-Toro D, Millar Vernetti P, Lui YW, Norcliffe-Kaufmann L, Kaufmann H (2020) The impact of supine hypertension on target organ damage and survival in patients with synucleinopathies and neurogenic orthostatic hypotension. Parkinsonism Relat Disord 75:97\u2013104. https:\/\/doi.org\/10.1016\/j.parkreldis.2020.04.011","journal-title":"Parkinsonism Relat Disord"},{"key":"800_CR32","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/s10286-018-0529-8","volume":"28","author":"A Fanciulli","year":"2018","unstructured":"Fanciulli A, Jordan J, Biaggioni I, Calandra-Buonaura G, Cheshire WP, Cortelli P, Eschlboeck S, Grassi G, Hilz MJ, Kaufmann H, Lahrmann H, Mancia G, Mayer G, Norcliffe-Kaufmann L, Pavy-Le Traon A, Raj SR, Robertson D, Rocha I, Struhal W, Thijs R, Tsioufis KP, van Dijk JG, Wenning GK (2018) Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): Endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). Clin Auton Res 28:355\u2013362. https:\/\/doi.org\/10.1007\/s10286-018-0529-8","journal-title":"Clin Auton Res"},{"key":"800_CR33","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1161\/HYPERTENSIONAHA.107.089961","volume":"50","author":"C Shibao","year":"2007","unstructured":"Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I (2007) Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 50:47\u201353. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.107.089961","journal-title":"Hypertension"},{"key":"800_CR34","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1002\/ana.25170","volume":"83","author":"L Norcliffe-Kaufmann","year":"2018","unstructured":"Norcliffe-Kaufmann L, Kaufmann H, Palma JA, Shibao CA, Biaggioni I, Peltier AC, Singer W, Low PA, Goldstein DS, Gibbons CH, Freeman R, Robertson D, Autonomic Disorders C (2018) Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 83:522\u2013531. https:\/\/doi.org\/10.1002\/ana.25170","journal-title":"Ann Neurol"},{"key":"800_CR35","doi-asserted-by":"publisher","first-page":"R817","DOI":"10.1152\/ajpregu.1991.260.4.R817","volume":"260","author":"MD Esler","year":"1991","unstructured":"Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman R, Meredith I, Lambert G, Cox HS, Jennings G (1991) Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol 260:R817-823. https:\/\/doi.org\/10.1152\/ajpregu.1991.260.4.R817","journal-title":"Am J Physiol"},{"key":"800_CR36","doi-asserted-by":"publisher","first-page":"R1429","DOI":"10.1152\/ajpregu.1995.268.6.R1429","volume":"268","author":"D Huangfu","year":"1995","unstructured":"Huangfu D, Goodwin WB, Guyenet PG (1995) Sympatholytic effect of tricyclic antidepressants: site and mechanism of action in anesthetized rats. Am J Physiol 268:R1429-1441. https:\/\/doi.org\/10.1152\/ajpregu.1995.268.6.R1429","journal-title":"Am J Physiol"},{"key":"800_CR37","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1002\/mds.23338","volume":"25","author":"H Nagayama","year":"2010","unstructured":"Nagayama H, Ueda M, Yamazaki M, Nishiyama Y, Hamamoto M, Katayama Y (2010) Abnormal cardiac [(123)I]-meta-iodobenzylguanidine uptake in multiple system atrophy. Mov Disord 25:1744\u20131747. https:\/\/doi.org\/10.1002\/mds.23338","journal-title":"Mov Disord"},{"key":"800_CR38","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s00401-006-0160-y","volume":"113","author":"S Orimo","year":"2007","unstructured":"Orimo S, Kanazawa T, Nakamura A, Uchihara T, Mori F, Kakita A, Wakabayashi K, Takahashi H (2007) Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy. Acta Neuropathol 113:81\u201386. https:\/\/doi.org\/10.1007\/s00401-006-0160-y","journal-title":"Acta Neuropathol"},{"key":"800_CR39","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/ana.24877","volume":"81","author":"H Kaufmann","year":"2017","unstructured":"Kaufmann H, Norcliffe-Kaufmann L, Palma JA, Biaggioni I, Low PA, Singer W, Goldstein DS, Peltier AC, Shibao CA, Gibbons CH, Freeman R, Robertson D, Autonomic Disorders C (2017) Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol 81:287\u2013297. https:\/\/doi.org\/10.1002\/ana.24877","journal-title":"Ann Neurol"},{"key":"800_CR40","doi-asserted-by":"publisher","first-page":"e1539","DOI":"10.1212\/WNL.0000000000006369","volume":"91","author":"JA Palma","year":"2018","unstructured":"Palma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H (2018) Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. Neurology 91:e1539\u2013e1544. https:\/\/doi.org\/10.1212\/WNL.0000000000006369","journal-title":"Neurology"},{"key":"800_CR41","first-page":"291","volume":"16","author":"IJ Kopin","year":"1982","unstructured":"Kopin IJ (1982) Evolving views of the metabolic fate of norepinephrine. Endocrinol Exp 16:291\u2013300","journal-title":"Endocrinol Exp"}],"container-title":["Clinical Autonomic Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10286-021-00800-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10286-021-00800-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10286-021-00800-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T11:13:08Z","timestamp":1623064388000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10286-021-00800-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["800"],"URL":"https:\/\/doi.org\/10.1007\/s10286-021-00800-x","relation":{},"ISSN":["0959-9851","1619-1560"],"issn-type":[{"value":"0959-9851","type":"print"},{"value":"1619-1560","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]},"assertion":[{"value":"1 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Drs. Kanodia, Lo, Norcliffe-Kaufmann and Bourdet are employees of Theravance Biopharma US, Inc. Dr. Vickery is an employee of Theravance Biopharma Ireland Limited.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Local IRB approvals were obtained.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have approved the final draft and agree to have these data published.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Theravance Biopharma US, Inc. (and its affiliates) will not be sharing individual de-identified participant data or other relevant study documents.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}}]}}