Clinical trial NCT01722669: Quercetin PK/PD Study in Healthy Adults and Patients With Hypercoagulable States
Official title: Pharmacokinetic and Pharmacodynamic Study of Oral Quercetin and Isoquercetin in Healthy Adults and Patients With Hypercoagulable States.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Healthy
Keywords: quercetin
isoquercetin
pharmacokinetic
pharmacodynamic
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
First posted: 2012-11-07
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: AUC
timeFrame: 24 hours
Secondary outcomes:
measure: Reductase Activity of PDI Using Dieosin Glutathione Disulfide
timeFrame: 2 hours. Not measured in D
measure: Platelet-induced Thrombin Generation (U/mL)
timeFrame: 4 hours
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Jeffrey Zwicker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight. 2017 Jan 12;2(1):e89373. doi: 10.1172/jci.insight.89373.