Inflammatory Response
Conditions
Brief summary
To investigate the effect of digoxin on pyruvate kinase isoform 2 (PKM2) binding to pro-inflammatory loci and innate immune inflammatory responses in the peripheral blood in healthy subjects.
Detailed description
To investigate the effect of orally administered digoxin on innate immune inflammatory responses in the peripheral blood of healthy subjects. We hypothesize the reduction in innate immune inflammatory responses will be expected in the peripheral blood with the effect of oral digoxin. To investigation how human peripheral blood immune cells change their inflammatory responses after exposure to digoxin in vitro.
Interventions
DRUGDigoxin
Participants will receive 3 mcg/Kg/day doses of oral digoxin
OTHERPlacebo
Oral placebo
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age \>18 y ≤ 70 years 2. subjects with normal serum creatinine, normal EKG and currently not taking any medication.
Exclusion criteria
1. Autoimmune liver disease (ANA \> 1/320) 2. Chronic viral hepatitis 3. Hepatocellular carcinoma 4. Complete portal vein thrombosis 5. Extrahepatic terminal disease 6. Pregnancy 7. Treatment with prednisolone or pentoxifyllin for more than 3 days prior to inclusion/start date 8. Active alcohol abuse (\>50 g/day for men and \>40 g/day for women) in the last 3 months 9. AST \> ALT and total bilirubin \> 3 mg/dl in the past 3 months 10. Liver biopsy and/or clinical picture consistent with alcoholic hepatitis 11. Lack of signed informed consent. 12. Known hypersensitivity to digoxin or other forms of digitalis, ventricular fibrillation. 13. Any significant medical conditions, any electrolyte abnormalities, over the counter medications, natural products and prescription drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production | after starting digoxin | Investigators will be take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | 6 weeks | Blood (25ml) will be obtained from healthy blood donors at one time. Human peripheral monocytes will be isolated using Polymorphprep™ density sedimentation according to the manufacturer's instructions. Data presented here are the mean concentrations. |
Countries
United States
Participant flow
Pre-assignment details
3 participants were consented but never started.
Participants by arm
| Arm | Count |
|---|---|
| Digoxin 3 mcg/Kg/Day Patients receiving oral digoxin 3 mcg/Kg/day
Digoxin: Participants will receive 3 mcg/Kg/day doses of oral digoxin | 6 |
| Digoxin 0.15 mcg Patients receiving oral digoxin 0.15 mcg/Kg/day
Digoxin: Participants will receive 0.15 mcg/Kg/day doses of oral digoxin | 6 |
| Placebo oral placebo
Placebo: Oral placebo | 7 |
| Total | 19 |
Baseline characteristics
| Characteristic | Digoxin 3 mcg/Kg/Day | Total | Placebo | Digoxin 0.15 mcg |
|---|---|---|---|---|
| Age, Continuous | 39.1 years STANDARD_DEVIATION 9 | 36.1 years STANDARD_DEVIATION 12 | 37.7 years STANDARD_DEVIATION 12 | 31.3 years STANDARD_DEVIATION 15 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 11 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 6 participants | 19 participants | 7 participants | 6 participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 14 | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production
Investigators will be take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.
Time frame: after starting digoxin
Population: No data for this outcome was collected.
Primary
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production
Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.
Time frame: 1 week after starting digoxin
Population: No data for this outcome was collected.
Primary
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production
Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.
Time frame: 2 weeks after starting digoxin
Population: No data for this outcome was collected.
Primary
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production
Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.
Time frame: 3 weeks after starting digoxin
Population: No data for this outcome was collected.
Secondary
Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro
Blood (25ml) will be obtained from healthy blood donors at one time. Human peripheral monocytes will be isolated using Polymorphprep™ density sedimentation according to the manufacturer's instructions. Data presented here are the mean concentrations.
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL10 | 366 pg/ml | Standard Deviation 293 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL4 | 1205 pg/ml | Standard Deviation 569 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL20 | 894 pg/ml | Standard Deviation 490 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL1 | 312 pg/ml | Standard Deviation 232 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL2 | 697 pg/ml | Standard Deviation 237 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | G-CSF | 35 pg/ml | Standard Deviation 19 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | GM-CSF | 42 pg/ml | Standard Deviation 15 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Granzyme B | 182 pg/ml | Standard Deviation 60 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Alpha | 26 pg/ml | Standard Deviation 31 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Gamma | 27 pg/ml | Standard Deviation 9 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-RA | 1074 pg/ml | Standard Deviation 290 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-6 | 1064 pg/ml | Standard Deviation 427 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AA | 238 pg/ml | Standard Deviation 294 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AB/BB | 128 pg/ml | Standard Deviation 75 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | TNF Alpha | 173 pg/ml | Standard Deviation 92 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-8 | 117 pg/ml | Standard Deviation 41 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Galactin 9 | 11977 pg/ml | Standard Deviation 4287 |
| Digoxin 3 mcg/Kg/Day | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL10 | 26069 pg/ml | Standard Deviation 6793 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL10 | 17528 pg/ml | Standard Deviation 9660 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL2 | 1351 pg/ml | Standard Deviation 483 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Gamma | 103 pg/ml | Standard Deviation 82 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AA | 1519 pg/ml | Standard Deviation 773 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL4 | 12180 pg/ml | Standard Deviation 9763 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | TNF Alpha | 2786 pg/ml | Standard Deviation 956 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-8 | 306 pg/ml | Standard Deviation 52 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL20 | 1205 pg/ml | Standard Deviation 569 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-RA | 6040 pg/ml | Standard Deviation 1785 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Galactin 9 | 20623 pg/ml | Standard Deviation 5876 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL1 | 1437 pg/ml | Standard Deviation 340 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Alpha | 97 pg/ml | Standard Deviation 61 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AB/BB | 908 pg/ml | Standard Deviation 539 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL10 | 2472 pg/ml | Standard Deviation 886 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Granzyme B | 1117 pg/ml | Standard Deviation 684 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-6 | 2797 pg/ml | Standard Deviation 831 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | G-CSF | 211 pg/ml | Standard Deviation 80 |
| Digoxin 0.15 mcg | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | GM-CSF | 142 pg/ml | Standard Deviation 39 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | G-CSF | 323 pg/ml | Standard Deviation 129 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | GM-CSF | 231 pg/ml | Standard Deviation 60 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Granzyme B | 2734 pg/ml | Standard Deviation 1582 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | TNF Alpha | 4040 pg/ml | Standard Deviation 1004 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Alpha | 174 pg/ml | Standard Deviation 109 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL10 | 2300 pg/ml | Standard Deviation 2230 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IFN Gamma | 229 pg/ml | Standard Deviation 99 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-RA | 12618 pg/ml | Standard Deviation 3485 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-8 | 420 pg/ml | Standard Deviation 24 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | IL-6 | 5006 pg/ml | Standard Deviation 1171 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL2 | 5790 pg/ml | Standard Deviation 2442 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL4 | 22328 pg/ml | Standard Deviation 7251 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AA | 2848 pg/ml | Standard Deviation 135 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CCL20 | 1761 pg/ml | Standard Deviation 471 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL1 | 2909 pg/ml | Standard Deviation 725 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | CXCL10 | 4452 pg/ml | Standard Deviation 1549 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | PDGF AB/BB | 1038 pg/ml | Standard Deviation 587 |
| Placebo | Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro | Galactin 9 | 25999 pg/ml | Standard Deviation 2645 |
Comparison: For IL10p-value: <0.01ANOVA