Purpose

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. 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.

Condition

Eligibility

Eligible Ages
Between 18 Years and 60 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Triple (Participant, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Galantamine
Galantamine 16mg/day - titrating: 4mg once a day for 2 weeks, titrate to 8mg once a day for 2 weeks, then 8mg twice a day for 8 more weeks
  • Drug: Galantamine
    4mg daily titrating up to 8mg twice a day
    Other names:
    • Razadyne
Placebo Comparator
Placebo
placebo (micro crystalline cellulose) - 1 pill once daily for 4 weeks, then 2 pills daily for 8 weeks
  • Drug: Placebo
    1 pill a day for 4 weeks, 2 pills a day for 8 weeks
    Other names:
    • sugar pill

Recruiting Locations

Vanderbilt University Medical Center
Nashville, Tennessee 37232
Contact:
Wendi Welch
wendi.m.welch@vumc.org

More Details

Status
Recruiting
Sponsor
Vanderbilt University Medical Center

Study Contact

Cyndya Shibao, MD
615-936-4584
cyndya.shibao@vumc.org

Detailed Description

Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies consistently shown that African Americans (AAs) have impaired endothelial function compared to whites. African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species (ROS), particularly superoxide which interferes with endothelial-derived nitric oxide signaling pathways. One of the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase contributes to vascular oxidation through the formation of highly immunogenic isolevuglandins (IsoLG-protein adducts) in peripheral mononuclear cells (PBMCs), which stimulates antigen presenting cells (APC) and inflammatory mediators. Inflammation and oxidative stress are modulated by the parasympathetic nervous system (PNS). The investigators and others found that AAs have reduced PNS activity compared with whites. The investigators preliminary data in obese AA women found that stimulation of the PNS cholinergic transmission with the acetylcholinesterase inhibitor, galantamine, blocked the production of oxidative stress and inflammatory cytokines induced by lipids. The overall goal of the current proposal is to determine if prolonged treatment with galantamine improves endothelial dysfunction and vascular oxidative stress in AAs. For this purpose, the investigators will conduct a proof-of-concept, blinded, randomized, placebo-controlled study to test the effect of 3-month treatment with galantamine (16 mg/day) on vascular oxidative stress and impaired vascular reactivity in AAs. Specifically, the investigators will evaluate whether galantamine treatment inhibits the activation of NADPH-IsoLG formation and the subsequent immunogenic responses in PBMCs. Furthermore, the investigators will determine if galantamine decreases markers of oxidative stress and inflammation in harvested endothelial cells (ECs) and improves vascular reactivity in the same study subjects. The planned studies will provide a comprehensive assessment of the mechanism underlying the effect of increased PNS cholinergic transmission on endothelial dysfunction. If the investigators' hypothesis is correct, and galantamine improves endothelial dysfunction in AAs, a population with a high risk for CVD, they will discover a novel mechanism that could alter the oxidative and immunogenic responses in this population and will offer a potential pathway for the development of more effective therapies aimed at decreasing CVD.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.