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

Abstract 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).

Download Full-text

Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with midodrine

The American Journal of Medicine ◽

10.1016/0002-9343(93)90230-m ◽

1993 ◽

Vol 95 (1) ◽

pp. 38-48 ◽

Cited By ~ 259

Author(s):

Joseph Jankovic ◽

Janice L. Gilden ◽

Bradley C. Hiner ◽

Horacio Kaufmann ◽

David C. Brown ◽

...

Keyword(s):

Orthostatic Hypotension ◽

Controlled Study ◽

Neurogenic Orthostatic Hypotension ◽

Double Blind ◽

Double Blind Placebo

Download Full-text

Neurogenic Orthostatic Hypotension: State of the Art and Therapeutic Strategies

Clinical Medicine Insights Cardiology ◽

10.1177/1179546820953415 ◽

2020 ◽

Vol 14 ◽

pp. 117954682095341

Author(s):

Dinesh K Kalra ◽

Anvi Raina ◽

Sumit Sohal

Keyword(s):

Blood Pressure ◽

Orthostatic Hypotension ◽

Clinical Features ◽

Autonomic Dysfunction ◽

State Of The Art ◽

Therapeutic Strategies ◽

Review Article ◽

Neurogenic Orthostatic Hypotension ◽

Standing Blood Pressure ◽

Secondary Causes

Neurogenic orthostatic hypotension (nOH) is a subtype of orthostatic hypotension in which patients have impaired regulation of standing blood pressure due to autonomic dysfunction. Several primary and secondary causes of this disease exist. Patients may present with an array of symptoms making diagnosis difficult. This review article addresses the epidemiology, pathophysiology, causes, clinical features, and management of nOH. We highlight various pharmacological and non-pharmacological approaches to treatment, and review the recent guidelines and our approach to nOH.

Download Full-text

Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure

Clinical Science ◽

10.1042/cs1010609 ◽

2001 ◽

Vol 101 (6) ◽

pp. 609-618 ◽

Cited By ~ 33

Author(s):

Stefano OMBONI ◽

Adrianus A.J. SMIT ◽

Johannes J. VAN LIESHOUT ◽

Jos J. SETTELS ◽

Gerard J. LANGEWOUTERS ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Output ◽

Stroke Volume ◽

Orthostatic Hypotension ◽

Peripheral Resistance ◽

Pulse Contour Analysis ◽

Pressure Profile ◽

Neurogenic Orthostatic Hypotension ◽

Contour Analysis ◽

Standing Blood Pressure

In the present study, we have assessed in patients with neurogenic orthostatic hypotension the haemodynamics underlying the reduced tolerance to standing after prolonged recumbency at night. In 10 patients with neurogenic orthostatic hypotension (age 33-68 years), of which seven were being treated with fludrocortisone and/or sleeping in the 12° head-up tilt position, 24h continuous non-invasive finger blood pressure was recorded by a Portapres device. Beat-to-beat blood pressure, heart rate, stroke volume, cardiac output and total peripheral vascular resistance obtained by pulse contour analysis were assessed during 5min of standing in the evening (at 22.30 hours) and in the morning (at 06.30hours). On average, the inverse of the normal 24h blood pressure profile was found, with a large diversity in blood pressure profiles among patients. Supine blood pressure values were similar, but standing blood pressure values were lower in the morning than in the evening (P < 0.01). This resulted from larger falls in stroke volume and cardiac output upon standing in the morning compared with the evening, while total peripheral resistance did not change. There was no relationship between the decrease in body weight during the night (mean 0.9kg; range 0.2-1.6kg) and the evening-morning difference in standing blood pressure. We conclude that, in patients with neurogenic orthostatic hypotension, the impaired tolerance to standing in the morning is due to larger falls in stroke volume and cardiac output. Not only nocturnal polyuria, but also a redistribution of body fluid, are likely mechanisms underlying the pronounced decreases in stroke volume and cardiac output after prolonged recumbency at night.

Download Full-text

Norepinephrine versus phenylephrine for maintenance of blood pressure during spinal anaesthesia for caesarean delivery - A randomized double blind controlled study

Indian Journal of Clinical Anaesthesia ◽

10.18231/j.ijca.2021.087 ◽

2021 ◽

Vol 8 (3) ◽

pp. 460-464

Author(s):

Devyani Desai ◽

Bhoomika Kalarthi

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Cardiac Output ◽

Systolic Blood Pressure ◽

Spinal Anesthesia ◽

Spinal Anaesthesia ◽

Caesarean Delivery ◽

Controlled Study ◽

Double Blind ◽

Significant Difference

: Currently phenylephrine is a preferred 1 line vasopressor for maintenance of blood pressure during spinal anaesthesia, may be associated with reflex bradycardia and decreased cardiac output, posing risk to mother or foetus. Norepinephrine may be an useful alternative as being potent alpha with weak beta adrenergic agonist activity. : This study compared the effectiveness of prophylactic and treatment boluses of norepinephrine and phenylephrine to maintain systolic blood pressure at or above 80% of baseline value during spinal anesthesia for cesarean delivery with the primary aim to compare cardiac output. Secondary aims were total doses of study drug required, neonatal outcome and perioperative complications.: Total 100, term pregnant women with ASA status II undergoing caesarean delivery under spinal anaesthesia were enrolled in this prospective, double blind controlled study. Patients were randomized to receive prophylactic bolus dose of norepinephrine (6 µg) or phenylephrine (100 µg) immediately after spinal anaesthesia. Systolic blood pressure, cardiac output and heart rate were monitored. Intermittent bolus doses were repeated whenever required. Student ‘t’ test and chi square test were used for analysing the data. : Both the drugs were able to maintain the systolic blood pressure ≥ 80% of baseline (p=0.356). Significant difference observed in cardiac output while comparing both the groups from 3 to 15 minutes after spinal anesthesia (p=0.014). The incidence of bradycardia was lower in norepinephrine group as compared to phenylephrine group (P=0.018). : Norepinephrine is as effective as phenylephrine for maintenance of blood pressure after spinal anaesthesia for caesarean delivery with stable heart rate and cardiac output.

Download Full-text

Systolic blood pressure response to laterally directed pressure applied to the cervical spine – a randomized, repeated-measures, double blind, placebo-controlled study

Physiotherapy ◽

10.1016/j.physio.2015.03.052 ◽

2015 ◽

Vol 101 ◽

pp. e1656-e1657

Author(s):

E. Yung ◽

M. Wong ◽

K. Wikfors ◽

H. Powell ◽

T. Smith ◽

...

Keyword(s):

Blood Pressure ◽

Cervical Spine ◽

Systolic Blood Pressure ◽

Repeated Measures ◽

Blood Pressure Response ◽

Pressure Response ◽

Controlled Study ◽

Double Blind ◽

Double Blind Placebo ◽

Directed Pressure

Download Full-text

Tomato Nutrient Complex Effect on Blood Pressure (P06-112-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-112-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Karin Linnewiel Hermoni ◽

Yoav Sharoni

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Healthy Volunteers ◽

Healthy Subjects ◽

Controlled Study ◽

Response Analysis ◽

Dependent Manner ◽

Double Blind ◽

Dose Dependent ◽

Different Doses

Abstract Objectives Examine the effect of a carotenoid-rich Tomato Nutrient Complex on blood pressure and perform a dose-response analysis and uncover the optimal effective supplementation dose in maintaining blood pressure within normal range among individuals with systolic blood pressure between 130–140 mmHg, otherwise healthy subjects. Methods In this double-blind, randomized, placebo-controlled study, different doses of the Tomato Nutrient Complex were examined, corresponding to 5 mg, 15 mg, and 30 mg lycopene. The effect of the tomato-derived treatment was compared with 15 mg of synthetic Lycopene and placebo over 8 weeks of treatment. In addition, we analyzed the bioavailability of the carotenoids following treatment with different doses of the Tomato Nutrient Complex in a group of 25 healthy volunteers. Volunteers were treated for four weeks with Tomato Nutrient Complex providing 2, 5 and 15 mg lycopene. Results Results indicate that treatment for 8 weeks with Tomato Nutrient Complex standardized to contain 15 mg or 30 mg of lycopene was associated with statistically significant reductions in mean SBP of 9.7 mmHg and 7 mmHg compared to baseline values respectively. Treatment with the lower dose Tomato Nutrient Complex standardized for 5 mg of lycopene, or treatment with 15 mg of synthetic lycopene as a standalone did not show a significant effect. In parallel, we analyzed the bioavailability of the carotenoids in healthy subjects. In a group of 25 healthy volunteers treated for 4 weeks with different doses of the Tomato Nutrient Complex. we identified a dose dependent and significant increase in blood level of lycopene, phytoene, and phytofluene. Conclusions Overall, the results suggest that the carotenoids in the Tomato Nutrient Complex are well absorbed in a dose dependent manner and that only the carotenoid levels achieved by the dose corresponding to 15 mg lycopene or more, is correlated to a beneficial effect on systolic blood pressure while lower doses and standalone lycopene are not enough to drive the effect. Funding Sources Lycored.

Download Full-text

Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension

Hypertension ◽

10.1161/hypertensionaha.119.14483 ◽

2021 ◽

Author(s):

Cyndya A. Shibao ◽

Jose-Alberto Palma ◽

Jorge E. Celedonio ◽

Jose Martinez ◽

Horacio Kaufmann ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Orthostatic Hypotension ◽

Diastolic Blood Pressure ◽

Pressor Response ◽

Norepinephrine Transporter ◽

Plasma Norepinephrine ◽

Neurogenic Orthostatic Hypotension ◽

Function Testing ◽

Cardiac Sympathetic Denervation

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.

Download Full-text