Inhibition of Sterile Inflammation by Digoxin

Study Overview
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Brief Summary
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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
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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 of how human peripheral blood immune cells change their inflammatory responses after exposure to digoxin in vitro.

Official Title
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Inhibition of Sterile Inflammation by Digoxin

Conditions
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Inflammatory Response

Intervention / Treatment
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* Drug: Digoxin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age >18 y ≤ 70 years subjects with normal serum creatinine, normal EKG and currently not taking any medication. Exclusion criteria Autoimmune liver disease (ANA > 1/320) Chronic viral hepatitis Hepatocellular carcinoma Complete portal vein thrombosis Extrahepatic terminal disease Pregnancy Treatment with prednisolone or pentoxifyllin for more than 3 days prior to inclusion/start date Active alcohol abuse (>50 g/day for men and >40 g/day for women) in the last 3 months AST > ALT and total bilirubin > 3 mg/dl in the past 3 months Liver biopsy and/or clinical picture consistent with alcoholic hepatitis Lack of signed informed consent. Known hypersensitivity to digoxin or other forms of digitalis, ventricular fibrillation. Any significant medical conditions, any electrolyte abnormalities, over the counter medications, natural products and prescription drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Digoxin 3 mcg/Kg/day<br>Patients receiving oral digoxin 3 mcg/Kg/day | Drug: Digoxin<br>* Different doses of oral digoxin to test if digoxin has an effect on the immune response of peripheral blood levels (PBLs).<br>|
| Active Comparator: Digoxin 0.15 mcg<br>Patients receiving oral digoxin 0.15 mcg/Kg/day | Drug: Digoxin<br>* Different doses of oral digoxin to test if digoxin has an effect on the immune response of peripheral blood levels (PBLs).<br>|
| Placebo Comparator: Placebo<br>oral placebo | Other: Placebo<br>* Oral placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower levels of spontaneous reactive oxygen species (ROS) production | We will be taking 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. | after starting digoxin | 
| Lower levels of spontaneous reactive oxygen species (ROS) production | We will be taking 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. | 1 week after starting digoxin | 
| Lower levels of spontaneous reactive oxygen species (ROS) production | We will be taking 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. | 2 weeks after starting digoxin | 
| Lower levels of spontaneous reactive oxygen species (ROS) production | We will be taking 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. | 3 weeks after starting digoxin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 weeks |