Inhibition of the norepinephrine transporter to treat neurogenic orthostatic hypotension: is this the end of the story?

We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improved standing blood pressure and lightheadedness in patients with neurogenic orthostatic hypotension (nOH). The purpose of the present study was to determine the predictors of the pressor response to atomoxetine. Patients with nOH who participated in the clinical trials ( https://www.clinicaltrials.gov ; Unique identifiers: NCT00223691 and NCT01316666) were included in this retrospective analysis. All subjects underwent autonomic function testing, plasma norepinephrine, systolic, diastolic blood pressure, and symptoms assessments, whereas seated and standing, before, and 60 minutes after a single dose of atomoxetine 18 mg. A subset of 25 patients underwent iodine-123–labeled metaiodobenzylguanidine scanning to estimate the degree of cardiac sympathetic denervation. A total of 99 subjects with nOH (67±9 years old, 40 women) participated in the study, 35 with multiple system atrophy, 52 with pure autonomic failure, and 12 with Parkinson disease. The average orthostatic decrease in their systolic blood pressure/diastolic blood pressure was −52±26/−22±15 mm Hg. Supine plasma norepinephrine levels predicted the standing systolic blood pressure (adjusted R 2 was 0.12, F [3,80]=4.66, P =0.007) and diastolic blood pressure (adjusted R 2 was 0.18, F [3, 80]=7.04, P =0.001) in response to atomoxetine. The increase in systolic blood pressure after atomoxetine was associated with the decrease in nOH-related symptoms ( R 2 =0.14, F [1,44]=8.16 P =0.007). In conclusion, plasma norepinephrine was modestly associated with the pressor response to atomoxetine in patients with nOH. Additionally, the improvement in nOH-related symptoms was associated with the increase in the pressor response to atomoxetine.

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

SSRN Electronic Journal ◽

10.2139/ssrn.3260799 ◽

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

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

Clinical Autonomic Research ◽

10.1007/s10286-021-00800-x ◽

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.

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