Healthy
Conditions
Keywords
quercetin, isoquercetin, pharmacokinetic, pharmacodynamic
Brief summary
The goal of this study is to evaluate how much quercetin or isoquercetin is absorbed after a single dose and evaluate for pharmacokinetic inhibition of protein disulfide isomerase. Pharmacodynamic studies will also be performed in an additional cohort of 10 patients with evidence of antiphospholipid antibodies
Detailed description
To compare the absorption and activity of quercetin or isoquercetin with or without ascorbic acid in healthy adults. Oral chews containing quercetin (500mg) or isoquercetin(500 mg total) with or without ascorbic acid will be given. Pharmacokinetic parameters (AUC, Cmax, Tmax, elimination half-life) will be determined over 24 hours (8 time points). Pharmacodynamic inhibition of protein disulfide isomerase activity will also be assessed. In addition to healthy subjects, a cohort of 10 individuals with antiphospholipid antibodies will participate. These participants will receive isoquercetin 1000 mg and have pharmacodynamics studies performed at time 0 and 4 hours. All study drugs will be provided by Quercegen Pharma.
Interventions
DRUGisoquercetin or quercetin
Single dose PK/PD study
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is willing to participate and provide informed consent * Subject is considered reliable and capable of adhering to the protocol per the judgment of the Investigator * Subjects in group D must exhibit good organ reserves (within prior 4 weeks) defined as: 1. Estimated GFR \>35 (formula), 2. Platelet count \>65 K/uL, 3. Hemoglobin \>10.5 grams/dL 4. Total bilirubin \<2.0 mg/dL * Minimum age 18 years old * Body mass index (BMI) between 18 and 35 kg/m2 * For cohort D (antiphospholipid antibodies) a. Subjects in group D must have at least one positive antiphospholipid antibody within the last 8 weeks and/or previous confirmed antibodies (2 or more occasions at least 12 weeks apart) : i. Positive lupus anticoagulant ii. anticardiolipin antibody IgM or IgG (\>40U GPL) iii. anti-β2 Glycoprotein1 antibody titer (\>35 units)
Exclusion criteria
* Pregnant. If female of child-bearing age, negative urinary pregnancy test prior to dosing of quercetin or isoquercetin * No history of malabsorptive gastrointestinal disorder * Currently taking aspirin, NSAIDS, warfarin, low-molecular weight heparin or other anticoagulants (such as direct thrombin inhibitors or factor X inhibitors) a. Note: Study subjects taking aspirin or NSAIDS, if treating physician concurs, are permitted to enroll if plan to hold for aspirin 10 days or NSAIDS 24 hours prior to dosing of quercetin/isoquercetin * Prescribed niacin for hyperlipidemia * Known HIV * History of sensitivity or intolerance to flavonoids, niacin or ascorbic acid * May not have uncontrolled intercurrent illness including, but not limited to ongoing or active infection, hepatitis, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 24 hours | AUC 0-24 hours of measured plasma quercetin aglycone for Arms A1, B1, A2, B2, C Collected at timepoints: baseline and 1, 2, 4, 6, 8, and 24 hours after dose. PK and PDI samples were not measured for Arm D (anti-phospholipid antibody cohort) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 2 hours. Not measured in D | Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide) |
| Platelet-induced Thrombin Generation (U/mL) | 4 hours | Thrombin induced thrombin generation measured in patient plasma |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Quercetin 500 mg (ARM A1) Single dose of quercetin PK/PD analysis | 5 |
| Isoquercetin 500 mg (ARM B1) Single dose of isoquercetin PK/PD analysis | 5 |
| Quercetin 500 mg + Ascorbic Acid (ARM A2) Single dose of quercetin + ascorbic acid PK/PD analysis | 5 |
| Isoquercetin 500 mg + Ascorbic Acid (ARM B2) Single dose of isqouercetin +ascorbic acid PK/PD analysis | 5 |
| Isoquercetin 1000 mg + Ascorbic Acid (ARM C) single dose isoquercetin + ascorbic acid PK/PD analyses | 10 |
| Antiphospholipid Antibody (ARM D) single dose isoquercetin +ascorbic acid in patients with antiphospholipid antibodies | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Quercetin 500 mg (ARM A1) | Total | Antiphospholipid Antibody (ARM D) | Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Quercetin 500 mg + Ascorbic Acid (ARM A2) | Isoquercetin 500 mg (ARM B1) |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 34 Participants | 4 Participants | 10 Participants | 5 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 17 Participants | 6 Participants | 5 Participants | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 17 Participants | 0 Participants | 3 Participants | 4 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 10 Participants | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 18 Participants | 5 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 20 Participants | 5 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 16 Participants | 1 Participants | 5 Participants | 2 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 6 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 10 | 0 / 6 |
Outcome results
Primary
AUC
AUC 0-24 hours of measured plasma quercetin aglycone for Arms A1, B1, A2, B2, C Collected at timepoints: baseline and 1, 2, 4, 6, 8, and 24 hours after dose. PK and PDI samples were not measured for Arm D (anti-phospholipid antibody cohort)
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quercetin 500 mg (ARM A1) | AUC | 4.78 uM hr/L | Standard Deviation 1.67 |
| Isoquercetin 500 mg (ARM B1) | AUC | 15.00 uM hr/L | Standard Deviation 8.94 |
| Quercetin 500 mg + Ascorbic Acid (ARM A2) | AUC | 5.41 uM hr/L | Standard Deviation 2.13 |
| Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | AUC | 16.34 uM hr/L | Standard Deviation 10.08 |
| Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | AUC | 40.3 uM hr/L | Standard Deviation 17.11 |
Secondary
Platelet-induced Thrombin Generation (U/mL)
Thrombin induced thrombin generation measured in patient plasma
Time frame: 4 hours
Population: 4 hours after single dose only measured in Arm C and Arm D
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quercetin 500 mg (ARM A1) | Platelet-induced Thrombin Generation (U/mL) | 0.30 U/mL | Standard Deviation 0.28 |
| Isoquercetin 500 mg (ARM B1) | Platelet-induced Thrombin Generation (U/mL) | 1.40 U/mL | Standard Deviation 2.14 |
Secondary
Reductase Activity of PDI Using Dieosin Glutathione Disulfide
Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide)
Time frame: 2 hours. Not measured in D
Population: 2 hours after oral ingestion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quercetin 500 mg (ARM A1) | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 31.9 Percent inhibition | Standard Deviation 24.14 |
| Isoquercetin 500 mg (ARM B1) | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 63.2 Percent inhibition | Standard Deviation 25.3 |
| Quercetin 500 mg + Ascorbic Acid (ARM A2) | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 16 Percent inhibition | Standard Deviation 31.8 |
| Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 8.3 Percent inhibition | Standard Deviation 15.03 |
| Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | 38 Percent inhibition | Standard Deviation 35 |