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Study Title and Description

Psychopharmacology of theobromine in healthy volunteers.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
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Primary Publication Information
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TitleData
Title Psychopharmacology of theobromine in healthy volunteers.
Author MJ Baggott,E Childs,AB Hart,E de Bruin,AA Palmer,JE Wilkinson,H de Wit,
Country
Year 2013
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Cardiovascular Design
Design Details
Question... Follow Up Answer Follow-up Answer
What outcome is being evaluated in this paper? Cardiovascular
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What is the objective of the study (as reported by the authors)? We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) Subjects were tested for recent drug use and pregnancy at the beginning of each session and completed physiological, cognitive, and mood measures before and at regular intervals after capsule administration according to the schedule in Table 1. We screened potential participants with semi-structured psychiatric interview, electrocardiogram, and a physical examination. To minimize the influence of population stratification on genotypic linkage analysis (Freedman et al. 2004), only Caucasians were accepted into the study. Individuals taking any prescription medications, working night shift or not fluent in English were not accepted. Participants were required to report consuming low levels of dietary caffeine or other methylxanthines to reduce potential confounds from tolerance and withdrawal. Candidates consuming more than 5 cups of coffee per week, or large quantities of chocolate, were excluded. Each subject ingested two sets of capsules on each session of either caffeine with placebo, or theobromine with placebo. Because caffeine peak plasma times are around 30 minutes post-administration whilst those for theobromine are around 2–3 h (Mumford et al. 1996), either theobromine or placebo was given first, followed 2.5 h later by caffeine or placebo. This was to align Cmax for caffeine and theobromine, or, in other words, to ensure that caffeine and theobromine plasma concentrations would peak at approximately the same time. Study treatments, given in random order, were: (1) Placebo at 1030 hours, then placebo at 1300 hours; (2) Theobromine (250 mg) at 1030 hours, then placebo at 1300 hours; (3) Theobromine (500 mg) at 1030 hours, then placebo at 1300 hours; (4) Theobromine (1,000 mg) at 1030 hours, then placebo at 1300 hours; (5) Placebo at 1030 hours, then caffeine (200 mg) at 1300 hours. Pharmaceutical-grade theobromine and caffeine (Fagron BV, Netherlands) were prepared according to GMP standards with identity and stability confirmed by HPLC/GC (Unilever R&D Vlaardingen). Heart rate and blood pressure were measured using a heart rate monitor (MiniLogger, Inc.). Participants were seated for at least 5 min, were required to be still and silent, and have both feet on the ground during each measurement. We collected a blood sample during the orientation session for DNA extraction and genotyping. DNA was extracted by the General Clinical Research Center of the University of Chicago. For four participants from whom blood was not available, we extracted DNA from saliva samples with the Oragene OG-250 kit (Oragene, DNA Genotek, Kanata, Ontario).We determined single nucleotide polymorphisms (SNPs) for ADORA2A (rs4822492 and rs5751876) with Applied Biosystems Custom TaqMan® SNP Genotyping Assay.
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How many outcome-specific endpoints are evaluated? 2
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Blood pressure (systolic and diastolic)
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List additional health endpoints (separately). 2 Heart rate
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List additional health endpoints (separately).3
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List additional health endpoints (separately).4
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List additional health endpoints (separately).5
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List additional health endpoints (separately).6
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Clinical, physiological, other Physiological
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What is the study design? Controlled Trial
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Randomized or Non-Randomized? RCT
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What were the diagnostics or methods used to measure the outcome? Objective
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Optional: Name of Method or short description Heart rate and blood pressure were measured using a heart rate monitor (MiniLogger, Inc.). Participants were seated for at least 5 min, were required to be still and silent, and have both feet on the ground during each measurement.
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Caffeine (general) Caffeine (general)
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Coffee, Chocolate, energy drink, gum, medicine/supplement, soda, tea, other?
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Measured or self reported? Measured
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Children, adolescents, adults, or pregnant included? Adults
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo vs. 200 mg caffeine
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) We excluded as outliers data exceeding the 4.5* interquartile range. Measures made more than once were expressed as change from baseline (time 0). For data from the drug questionnaires and physiological measures, maximum change from baseline (Emax) was calculated, using the baseline, 180-, and 255-min measures. We analyzed data using mixed-effects models in R 2.15.2 (R Development Core Team 2012) with Condition as a fixed effect and Participant as a random effect using a two-tailed test with α=0.05. When the F test showed a main effect of Condition, conditions were compared pairwise with post hoc comparisons using Tukey’s HSD test corrected for multiple comparisons using the single-step method.
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What conflicts of interest were reported? Not discussed.
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Refid 23420115
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What were the sources of funding? This research was supported by Unilever R and D. Additional support from T32 MH020065 (MJB), DA02812 (HdW), T32 DA007255 (ABH), and DA021336 (AAP).
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