Food Matrix Effect on Flavanol Absorption, Metabolism and Excretion: Methylxanthines

Study Overview
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Brief Summary
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Dietary intervention study in healthy young adult males to evaluate concentration of flavanol metabolites in plasma and urine after single acute intakes of methylxanthines.

Detailed Description
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Flavonoids, including the sub groups of Flavanols (F) are plant-derived compounds commonly present in the human diet. Examples of F-containing foods and beverages are apples, chocolate, tea, wine, berries, pomegranate and nuts. The consumption of F-containing foods and beverages has been associated with improvements in cardiovascular health. In this context, there exists a great interest in describing the absorption, metabolism and excretion of F in humans, as it is thought that F-derived metabolites present in circulation are the mediators of F-beneficial effects in humans. Recently, the investigators described a series of F-derived metabolites in circulation that are present after the consumption of a single acute intake amount of F in humans as well as F-metabolites derived from the metabolic activity of the gut microbiome. A key question, however, is if the metabolites the investigators observed after a single acute feeding are the same as those that occur in individuals who consume F-rich diets on a regular basis. Studies investigating the metabolism of numerous other xenobiotics have shown that the profile of metabolites can greatly vary over time, as well as with the amount of the xenobiotic ingested. In this context, the investigators submit it is important to assess whether or not there are food matrix-dependent effects on the levels and profile of F-derived metabolites in humans. The investigators suggest the information that will be obtained from the outlined work will be particularly timely given ongoing discussion concerning the possible generation of dietary recommendations for F-rich foods and increasing interest in the putative health effects of F intake in humans. Following the beginning of the trial, an advanced method to analyze cocoa flavanols was accredited by AOAC International as a First Action Official Method of Analysis https://doi.org/10.1093/jaoacint/qsaa132). This updated method relies on a reference material (RM8403) recently standardized and made commercially available by the U.S. National Institute of Standards and Technology. While the actual cocoa flavanol content of our intervention remained unchanged throughout the trial, the application of this new analytical method led to expected changes in how the total cocoa flavanol content is now reported. Applying AOAC 2020.05/RM8403 to our intervention, the total cocoa flavanol content of select arms in our trials have been updated accordingly.

Official Title
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Food Matrix Effect on Flavanol Absorption, Metabolism and Excretion: Methylxanthines

Conditions
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Healthy

Intervention / Treatment
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* Other: CF Control
* Other: CF-Theobromine
* Other: CF-Caffeine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No prescription medications BMI 18.5 - 29.9 kg/m2 Weight ≥ 110 pounds previously consumed cocoa, peanut, parsley, celery and chamomile products with no adverse reactions Exclusion Criteria: Adults unable to consent Prisoners Non-English speaking* BMI ≥ 30 kg/m2 Performing vigorous physical activity (i.e. more than 6 MET; metabolic equivalence of task as defined by CDC and ACSM guidelines (http://www.cdc.gov/physicalactivity/everyone/glossary/index.html#vig-intensity; and http://www.cdc.gov/nccdphp/dnpa/physical/pdf/PA_Intensity_table_2_1.pdf ) for more than 3 days a week. Dietary allergies including those to nuts, cocoa and chocolate products, parsley, celery and chamomile. Active avoidance of coffee and caffeinated soft drinks Under current medical supervision A history of cardiovascular disease, stroke, renal, hepatic, or thyroid disease History of clinically significant depression, anxiety or other psychiatric condition History of Raynaud's disease History of difficult blood draws Indications of substance or alcohol abuse within the last 3 years Current use of herbal, plant or botanical supplements (multi-vitamin/mineral supplements are allowed) Blood Pressure > 140/90 mm Hg GI tract disorders, previous GI surgery (except appendectomy) Self-reported malabsorption (e.g. difficulty digesting or absorbing nutrients from food, potentially leading to bloating, cramping or gas) Diarrhea within the last 3 months, or antibiotic intake within the last 3 months Vegetarian, Vegan, food faddists, individuals using non-traditional diets, on a weight loss diet or individuals following diets with significant deviations from the average diet Metabolic panel and cholesterol results or complete blood counts that are outside of the normal reference range and are considered clinically relevant by the study physician Cold, flu, or upper respiratory condition at screening Currently participating in a clinical or dietary intervention study

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

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: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Dietary intervention study in healthy young adult males
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CF Control<br>CF Control: 587 mg of cocoa flavanols (101 mg epicatechin), <1 mg caffeine and <1 mg theobromine | Other: CF Control<br>* CF Control: 587 mg of cocoa flavanols, <1 mg caffeine and <1 mg theobromine<br>|
| Experimental: CF-Theobromine<br>CF-Theobromine: 575 mg of cocoa flavanols (102 mg epicatechin), 11 mg caffeine and 93 mg theobromine | Other: CF-Theobromine<br>* CF-Theobromine: 575 mg of cocoa flavanols, 11 mg caffeine and 93 mg theobromine<br>|
| Experimental: CF-Caffeine<br>CF-Caffeine: 587 mg of cocoa flavanols (101 mg epicatechin), 112 mg caffeine and <1 mg theobromine(Experimental) | Other: CF-Caffeine<br>* CF-Caffeine: 587 mg of cocoa flavanols, 112 mg caffeine and <1 mg theobromine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flavanol metabolites in plasma | Plasma concentration of flavanol metabolites | Before to 6 h post test material intake | 
| Flavanol metabolites in urine | Amount of flavanols metabolites excreted in urine | 12 h before to 24 h post test material intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methylxanthines in plasma | Plasma concentration of methylxanthines and methylxanthine metabolites | Before to 6 h post test material intake | 
| Methylxanthines in urine | Amount of methylxanthines and methylxanthine metabolites excreted in urine | 12 h before to 24 h post test material intake | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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flavanol, ADME, polyphenols, cocoa, epicatechin, methylxanthine, caffeine