Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Purpose In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension. Methods A multicenter ascending-dose trial (range 1–20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety. Results Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6–52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration. Conclusion Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure. Trial registration NCT02705755 (first posted March 10, 2016).

Neurogenic cardiovascular disorders in α-synucleinopathies: diagnostic and therapy issues

Diagnostics and treatment of the neurogenic cardiovascular disorders in α-synucleinopathies are difficult due to the early-onset of autonomic deficiency and masking under other diseases. The paper discusses the development and progression mechanisms of manifestations of neurogenic cardiovascular pathology. The main forms include neurogenic orthostatic hypotension, neurogenic hypertension in supine position (recumbent neurogenic hypertension) and its nocturnal variant. The existing and promising diagnostic approaches and related difficulties are presented. The possible relationship of cardiovascular disorders in α-synucleinopathies and their manifestations is shown. A possible diagnostic algorithm and possible non-drug and drug treatment and prevention approaches in neurogenic cardiovascular deficiency in α-synucleinopathies are presented. The importance of a multidisciplinary approach is emphasized.