Effect of Antioxidants on Ocular Blood Flow, Endothelial Function, and Cytokine Levels in LPS Induced Inflammatory Model in Humans.

Study Overview
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Brief Summary
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Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates, has been implicated in many disease processes, especially age-related disorders. Many trials investigating use of antioxidants in protecting different tissues against oxidative stress have been conducted, but the results are ambiguous. Inflammation is generally associated with enhanced oxidative stress and widespread endothelial dysfunction. In the present study, the infusion of LPS, which is a cell wall component of Gram-negative bacteria and a major mediator in the pathogenesis of septic shock, will be used as a standardized experimental model of systemic inflammatory response in humans. The assessment of outcome parameters will include measurements of ocular blood flow, forearm blood flow and plasma concentration of cytokines. Measurements of ocular hemodynamics provide an unique chance to investigate local blood flow in humans non-invasively. Moreover, the retina is especially susceptible to oxidative stress because of its high consumption of oxygen, its high polyunsaturated fatty acid content, and its exposure to visible light. Evidence from literature clearly supports a role for oxidative stress in pathophysiology of several ocular diseases including diabetic retinopathy and age-related macular degeneration. To investigate the retinal vascular reactivity we will use systemic hyperoxia as a stimulus. The measurement of forearm blood flow will be use to assess endothelial function. The main study objective is to investigate the effect of oral vitamins and minerals supplementation on impaired retinal vascular reactivity after LPS administration.

Official Title
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Effect of Antioxidants on Ocular Blood Flow, Endothelial Function, and Cytokine Levels in LPS Induced Inflammatory Model in Humans.

Conditions
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Retina, Regional Blood Flow, Endotoxin, Escherichia Coli

Intervention / Treatment
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* Drug: vitamin and mineral supplement
* Drug: Escherichia coli Endotoxin (LPS)
* Drug: 100% O2
* Drug: nitroglycerin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged between 18 and 35 years, nonsmokers Body mass index between 15th and 85th percentile Normal findings in the medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant Normal ophthalmic findings, ametropia < 3 Dpt Exclusion Criteria: Regular use of medication, abuse of alcoholic beverages, participation in a clinical trial in the 3 weeks preceding the study Treatment in the previous 3 weeks with any drug, vitamins and minerals supplements as well Symptoms of a clinically relevant illness in the 3 weeks before the first study day History of hypersensitivity to the trial drug or to drugs with a similar chemical structure History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with, distribution, metabolism or excretion of study drugs Blood donation during the previous 3 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: vitamin and mineral supplement<br>* dose: 4 tablets daily for two weeks vitamin A 7160 IU, vitamin C 113mg, vitamin E 100IU, zinc 17.4mg, copper 0.4mg<br>* Other names: Ocuvite preservision;Drug: Escherichia coli Endotoxin (LPS)<br>* dose: 2 ng/kg (corresponding to 20 IU/kg), intravenous bolus over 5 minutes on both study days<br>* Other names: US Standard Endotoxin;Drug: 100% O2<br>* breathing for 30 minutes, 2 breathing periods on both study days<br>Drug: nitroglycerin<br>* dose: 0,8 mg sublingual, applied during FMD measurements on both study days<br>* Other names: Nitrolingual Pump Spray;|
| Placebo Comparator: 2<br> | Drug: Escherichia coli Endotoxin (LPS)<br>* dose: 2 ng/kg (corresponding to 20 IU/kg), intravenous bolus over 5 minutes on both study days<br>* Other names: US Standard Endotoxin;Drug: 100% O2<br>* breathing for 30 minutes, 2 breathing periods on both study days<br>Drug: nitroglycerin<br>* dose: 0,8 mg sublingual, applied during FMD measurements on both study days<br>* Other names: Nitrolingual Pump Spray;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retinal blood flow |  | in total 8x on 2 study days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Choroidal blood flow |  | in total 4x on 2 study days | 
| Flow mediated dilation (FMD) of brachial artery assessed with ultrasound |  | in total 4x on 2 study days | 
| Blood pressure, heart rate |  | on 2 study days | 
| Body temperature |  | on 2 study days | 
| Concentration of cytokines in plasma |  | on 2 study days |