scholarly journals Norepinephrine reuptake blockade to treat neurogenic orthostatic hypotension

2021 ◽  
Author(s):  
Graeme Eisenhofer ◽  
David S. Goldstein
Keyword(s):  
Orthostatic Hypotension ◽  
Neurogenic Orthostatic Hypotension ◽  
Norepinephrine Reuptake

scholarly journals Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension

2021 ◽  
Author(s):  
Arthur Lo ◽  
Lucy Norcliffe-Kaufmann ◽  
Ross Vickery ◽  
David Bourdet ◽  
Jitendra Kanodia
Keyword(s):  
Orthostatic Hypotension ◽  
Sympathetic Neurons ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Treatment Phase ◽  
Target Population ◽  
Neurogenic Orthostatic Hypotension ◽  
Open Label ◽  
Once Daily ◽  
Norepinephrine Reuptake

Abstract Purpose Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. Methods Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks 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. Results Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6–9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). Conclusions 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 nOH.

Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants: Novel Genetic Cause of Neurogenic Orthostatic Hypotension

2018 ◽  
Author(s):  
Cyndya Shibao ◽  
John A. Phillips ◽  
Joy D. Cogan ◽  
John H. Newman ◽  
Rizwan Hamid ◽  
...  
Keyword(s):  
Orthostatic Hypotension ◽  
Genetic Variants ◽  
Neurogenic Orthostatic Hypotension

scholarly journals Decreased Noradrenaline (Norepinephrine) Synthesis in Neurogenic Orthostatic Hypotension

Circulation ◽  
1968 ◽  
Vol 38 (3) ◽  
pp. 592-603 ◽  
Author(s):  
McC. GOODALL ◽  
W. R. HARLAN ◽  
HAROLD ALTON
Keyword(s):  
Orthostatic Hypotension ◽  
Neurogenic Orthostatic Hypotension
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