Human Intervention Study From Report of the EU

Human Intervention Study From Report of the EU reviewers (Midterm review 14 -02 -2002, Brussels) “The human studies need careful thought otherwise there is a danger of the project appearing to have failed simply because it did not provide the hoped for cure for heart disease and cancer” 1

Human Intervention Study History - Garlic would influence lipid metabolism / atherosclerosis - Proposed study: - 2 * 24 apparently healthy subjects with increased risk (mildly hypercholesterolemic, smoking) - parallel trial (24 garlic / 24 placebo) - biochemical measures lipid metabolism / inflammation 2

Human Intervention Study Current situation: - No indications that ‘garlic’ influences lipid metabolism Þ (human) intervention study without rationale is unethical; previous proposal not feasible - New situation requires evaluation; other type of intervention study 3

Human Intervention Study Considerations: - Indications that ‘garlic’ may influence inflammation - Cardiovascular disease (atherosclerosis; AS) shares common features with inflammation; CRP is primary endpoint - Current treatment strategies for AS also focus on inflammation (for example: lipid lowering drugs; statins) 4

Human Intervention Study Garlic and Inflammation/Atherosclerosis - parallel design; 3 groups (n=30); risks groups; high doses!! 1. garlic powder (Kwai / EU? ? ) 2. aged garlic extract (Kyolic? ? ) 3. control power = 0. 87 - 0. 72 for 30 - 25% CRP-reduction 5

Human Intervention Study - Garlic powder (Kwai / EU? ? ) 1. - all compounds present in fresh garlic / sulphurrich compounds (Alliin) preserved 2. - Aged garlic extract (Kyolic? ? ) - fermented garlic (S-allyl cystein) 6

Human Intervention Study - Recruitment: advertisements - Medical screening - 2 -week run-in period - Duplicate sampling (10 -14 days apart) / measurements - Randomisation - Duplicate sampling / measurements HALF-WAY (6 wks) & END treatment period (12 wks) 7

Garlic and Inflammation - Biomarkers for inflammation - C-Reactive Protein (!!) - Fibrinogen - Cytokines after whole blood stimulation with LPS (TNF- ; IL-10) - Biomarkers for endothelial function - von Willebrand Factor 8

Additional biomarkers; atherosclerosis - Clinical measures (ECG / HRV / BP) - Routine lab (chol / HDL-C / triglyc / LDH etc. ) - PAI / s-VCAM / s-ICAM / s-Selectine - SAA - ox-LDL (plasma) / isoprostanes (urine) - soluble CD 40 L (platelets) 9

Additional biomarkers; atherosclerosis - IL-18 (IL-6) - m. RNA - leukocytes - gene array - (Metabolites) of garlic compounds in urine (and blood? ) 10

Additional biomarkers; other Cancer biomarkers - phase II enzymes as glutathione S-transferase and quinone reductase (plasma and lymphocytes) - DNA damage (lymphocytes) - comet assay - Anti-mutagenic properties (urine) - Ames test 11

Points to discuss - Design -Positive control? (statin) - Study group Characteristics - mildly obese, smokers, postmenopausal women - Intervention material and supplier - Lichtwer and Wakanuga? ; EU-preparation? ) - Dosages - 6 g/day aged garlic extract / 2 -4 g garlic powder 12

Points to discuss - Questions - is there a garlic effect? - is it dependent on the preparation? - Are these the questions we want to answer? 13