Obesity
Conditions
Brief summary
The investigators will test the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity and reduce oxidation in AAW compared to whites.
Detailed description
Obesity has a greater detrimental impact on the health of African American women (AAW) than on any other racial or gender group. Nearly 80% of AAW are overweight or obese. Reduced insulin sensitivity is more prevalent among AAW as compared to white women and men of both races. This condition puts AAW at increased risk for the development of type 2 diabetes mellitus. The exact mechanism underlying these pathophysiological differences remains unknown. The investigators have found that obese AAW have decreased parasympathetic nerve (PNS) activity compared to whites and recent studies in animal models showed that the PNS confers protection against oxidative stress. In our AA cohort, PNS activity was directly correlated with insulin sensitivity in obese AAW even after controlling for differences in age, blood pressure and visceral adiposity. Equally important, the investigators also showed that the decrease in insulin sensitivity was associated with increased oxidative stress as measured by plasma levels of F2-isoprostanes. Taken together these findings lead us to hypothesize that the decreased PNS activity in obese AAW compared to white women has deleterious effects on oxidative stress and insulin sensitivity.The investigators will test the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity and reduce oxidation in AAW compared to whites.
Interventions
DRUGGalantamine
16 mg po prior to the infusion of intralipid
DRUGPlacebo Oral Capsule
Placebo oral capsule prior to the infusion of intralipid/heparin
DRUGIntralipid
Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine
DRUGHeparin
heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Sponsors
Doris Duke Charitable Foundation
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Female * African American or white (race will be self-defined, but only subjects who report both parents of the same race will be included) * 18-60 years old * BMI 30-45 Kg/m2 * Not pregnant or breastfeeding
Exclusion criteria
* Pregnant or breastfeeding * Diabetes diagnosis (defined by the American Diabetes Association (ADA) criteria)38 * Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy. * Arrhythmia (first-, second-, and third-degree atrioventricular (AV) block) * Significant weight change \>5% in the past 3 months * Impaired hepatic function (AST and/or Alanine transaminase (ALT) \> one and one half times (1.5X) upper limit of normal range) * Impaired renal function (eGFR \<60ml/min) * Users of strong inhibitors of Cytochrome P450 3A4 (CYP3A4) or cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) * Users of other acetylcholinesterase inhibitors such as pyridostigmine or bethanechol * History of alcohol or drug abuse * Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study * Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxidative Stress: Baseline to 2 Hours | Baseline to 2 hours | Measure F-2 isoprostanes as a marker of oxidation |
| Change in Oxidative Stress: Baseline to 4 Hours | Baseline to 4 hours | Measure F-2 isoprostanes as a marker of oxidation |
Countries
United States
Participant flow
Pre-assignment details
52 participants were screen failures and did not receive an intervention.
Participants by arm
| Arm | Count |
|---|---|
| Galantamine 16 mg Then Placebo (African-American) Galantamine 16 mg po one time dose then placebo on 2nd visit
Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine
Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine | 7 |
| Galantamine 16 mg Then Placebo (White) Galantamine 16 mg po one time dose then placebo on 2nd visit
Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine
Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine | 6 |
| Placebo Then Galantamine 16 mg (African-American) Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit
Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine
Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine | 7 |
| Placebo Then Galantamine 16 mg (White) Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit
Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine
Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine | 3 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Galantamine 16 mg Then Placebo (African-American) | Galantamine 16 mg Then Placebo (White) | Placebo Then Galantamine 16 mg (African-American) | Placebo Then Galantamine 16 mg (White) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 7 Participants | 3 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 0 Participants | 7 Participants | 0 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 6 Participants | 0 Participants | 3 Participants | 9 Participants |
| Region of Enrollment United States | 7 participants | 6 participants | 7 participants | 3 participants | 23 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 7 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 9 | 0 / 14 | 0 / 9 |
| other Total, other adverse events | 4 / 14 | 6 / 9 | 2 / 14 | 2 / 9 |
| serious Total, serious adverse events | 0 / 14 | 0 / 9 | 0 / 14 | 0 / 9 |
Outcome results
Primary
Change in Oxidative Stress: Baseline to 2 Hours
Measure F-2 isoprostanes as a marker of oxidation
Time frame: Baseline to 2 hours
Population: 2 white participants dropped out due to nausea. 1 African-American was withdrawn, MD decision.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Galantamine 16 mg (African-American) | Change in Oxidative Stress: Baseline to 2 Hours | -0.003 pg /ml | Standard Deviation 0.012 |
| Galantamine 16 mg (White) | Change in Oxidative Stress: Baseline to 2 Hours | -0.006 pg /ml | Standard Deviation 0.018 |
| Placebo (African-American) | Change in Oxidative Stress: Baseline to 2 Hours | 0.01 pg /ml | Standard Deviation 0.018 |
| Placebo (White) | Change in Oxidative Stress: Baseline to 2 Hours | -0.006 pg /ml | Standard Deviation 0.01 |
Primary
Change in Oxidative Stress: Baseline to 4 Hours
Measure F-2 isoprostanes as a marker of oxidation
Time frame: Baseline to 4 hours
Population: 1 white participant did not have 4 hour F-2 isoprostanes drawn after receiving placebo. 2 white participants dropped out due to nausea. 1 African-American was withdrawn, MD decision.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Galantamine 16 mg (African-American) | Change in Oxidative Stress: Baseline to 4 Hours | 0 pg/ml | Standard Deviation 0.016 |
| Galantamine 16 mg (White) | Change in Oxidative Stress: Baseline to 4 Hours | -0.008 pg/ml | Standard Deviation 0.014 |
| Placebo (African-American) | Change in Oxidative Stress: Baseline to 4 Hours | 0.003 pg/ml | Standard Deviation 0.005 |
| Placebo (White) | Change in Oxidative Stress: Baseline to 4 Hours | -0.008 pg/ml | Standard Deviation 0.014 |