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ACTIVE NOT RECRUITING

NCT04769206

PHASE1/PHASE2

Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans

Sponsor: Vanderbilt University Medical Center

View on ClinicalTrials.gov

Summary

Specific Aim 1: To test the hypothesis that prolonged (3-month) treatment with galantamine inhibits NADPH IsoLG-protein adducts formation and improves markers of endothelial cell (EC) dysfunction in AAs. Aim 1a: The investigators will determine if galantamine inhibits NADPH IsoLG-protein adducts formation, superoxide production, and immune cell activation compared to placebo. For this purpose, the investigators will study peripheral blood mononuclear cell (PBMC), a critical source of systemic oxidative stress, collected from study participants. Aim 1b: The investigators will determine if galantamine reduces intracellular Iso-LGs, ICAM-1, and 3-nitrotyrosine, a marker of vascular oxidative stress, in ECs harvested from study participants. Specific Aim 2: To determine if prolonged (3-month) treatment with galantamine improves endothelial dysfunction as measured by vascular reactivity in AAs. The investigators will measure vascular reactivity in response to ischemia in two vascular beds: (a) in conduit arteries (brachial artery) using brachial artery diameter flow-mediated dilation (FMD), and (b) in the microvasculature (MBV) using contrast-enhanced ultrasonography in skeletal muscle. Sub-study (optional) Will study the effect of trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress This proposal will study a novel mechanism that could alter the oxidative and immunogenic responses that contributes to endothelial dysfunction in AAs and will offer a potential pathway for the development of more effective therapies aimed at decreasing the progression of endothelial dysfunction to cardiovascular disease in this population.

Key Details

Gender

All

Age Range

18 Years - 60 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2021-12-20

Completion Date

2026-07-30

Last Updated

2026-03-12

Healthy Volunteers

Yes

Conditions

Endothelial Dysfunction

Interventions

DRUG

Galantamine

4mg daily titrating up to 8mg twice a day

DRUG

Placebo

1 pill a day for 4 weeks, 2 pills a day for 8 weeks

DEVICE

TENS 7000

The FDA-approved TENS 7000 device will be used for Trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress. This device will be supplemented with ear clip electrodes. The site of the stimulation for such electrodes are the tragus or concha. The device will have built in safety controls to minimize additional risks to the subjects (as per FDA guidance on stimulators). We will use typical stimulation conditions (30 Hz, 300 µs) and amplitude dependent on perception threshold.

Inclusion Criteria: 1. African American women and men 2. Age 18 to 60 years old 3. BMI \>28 Exclusion Criteria: 1. Individuals with a history of physician diagnosed myocardial infarction, angina, heart failure, stroke, or transient ischemic attack, or who had undergone an invasive procedure for CVD (coronary artery bypass graft, angioplasty, valve replacement, pacemaker placement or other vascular surgeries) 2. Uncontrolled hypertension defined as persistent blood pressure \>140/90 despite the use of anti-hypertensive agents. 3. Diabetes Mellitus type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater hemoglobin A1C (HbA1C) 6.5% or above or the use of anti-diabetic medication 4. The use of nitrates. 5. The metabolism of galantamine is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. We will exclude subjects who have impaired hepatic function and/or who are currently using strong inhibitors of CYP3A4 and CYP2D6 (e.g. ketoconazole and paroxetine, respectively). 6. Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control. 7. Post-menopausal women. 8. The use of any other central or peripheral acetylcholinesterase inhibitor (donezepil (Aricept(R)), pyridostigmine (Mestinon(R)), rivastigmine (Exelon(R)), tacrine (Cognex(R)). 9. First, second or third-degree AV block detected during the screening visit with an ECG 10. Seizures or history of seizures. 11. Current smokers defined as those who smoked a cigarette in the last 30 days. 12. History of recurrent syncope. 13. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack. 14. History of cardiac shunts. 15. Allergy to eggs or soy. 16. Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>3.0 x upper limit of normal range) 17. Impaired renal function test (eGFR\<60 mL/min/1.73m2) 18. Anemia (hematocrit \<34%) 19. Ongoing substance abuse. 20. Treatment with any investigational drug in the one month preceding the study 21. Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study 22. Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Locations (1)

Chaney Johnson

Nashville, Tennessee, United States