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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”

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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

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Human Intervention Study

Current situation:

- No indications that ‘garlic’ influences lipid metabolism

(human) intervention study without rationale is unethical; previous proposal not feasible

- New situation requires evaluation; other type of intervention study

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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)

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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

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Human Intervention Study

- Garlic powder (Kwai / EU??)

- all compounds present in fresh garlic / sulphur-rich compounds (Alliin) preserved

- Aged garlic extract (Kyolic??)- fermented garlic (S-allyl cystein)

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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)

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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

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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 CD40L (platelets)

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Additional biomarkers; atherosclerosis

- IL-18 (IL-6)

- mRNA - leukocytes - gene array

- (Metabolites) of garlic compounds in urine (and blood?)

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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

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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

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Points to discuss

- Questions

- is there a garlic effect?

- is it dependent on the preparation?

- Are these the questions we want to answer?