Recombinant Human Superoxide Dismutase (rhSOD) and Vascular Reactivity

Study Overview
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Brief Summary
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Inflammation is characterised by an increased risk for cardiovascular events. Dysfunction of the vascular endothelium caused by oxidative stress might provide a mechanistic link. In acute and chronic inflammation, oxidative stress occurs when the production of reactive oxygen species [ROS] (including superoxide anions [O2-]) exceeds the capacity of the endogenous antioxidant defense systems, resulting in ROS-mediated damage. Recombinant human superoxide dismutase (rhSOD) has shown potent antioxidant properties in in-vitro and animal studies and has been tested in phase I clinical trials in humans. rhSOD could offer a therapeutic option for vascular dysfunction in diseases associated with increased oxidative stress. The investigators, therefore, want to test if the hyporesponsiveness to vasoactive drugs (norepinephrine, acetylcholine and glyceroltrinitrate) during acute inflammation by low-dose lipopolysaccharide (LPS) is due to the increased production of superoxide anions, which could be scavanged by the radical scavenger rhSOD.

Official Title
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Impact of rhCu/Zn SOD on Inflammation-Induced Impairment of Vascular Reactivity

Conditions
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Inflammation

Intervention / Treatment
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* Drug: LPS 2 ng/kg intravenous (IV) bolus
* Drug: rhSOD 82,000 IU (8.2 mg)/min intraarterially
* Drug: Norepinephrine 60, 120, 240 pmol/min intraarterially over 5 min/dose level (two times; pre-dose and +3.5 hrs)
* Drug: Acetylcholine 6.25, 12.5, 25 nmol/min intraarterially over 3 min/dose level (two times; pre-dose and +3.5 hrs)
* Drug: Glyceroltrinitrate (nitroglycerine) 4, 8, 16 nmol/min over 3 min/dose level (two times; pre-dose and +3.5 hrs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged between 18 and 45 years Nonsmokers Body mass index between 15th and 85th percentile Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant Exclusion Criteria: Regular use of medication, abuse of alcoholic beverages, or participation in a clinical trial in the 3 weeks preceding the study Evidence of hypertension, pathologic hyperglycemia, or hyperlipidemia Treatment in the previous 3 weeks with any drug Symptoms of a clinically relevant illness in the 3 weeks before the first study day 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 History of hypersensitivity to the trial drug or to drugs with a similar chemical structure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: LPS 2 ng/kg intravenous (IV) bolus|nan|
|Drug: rhSOD 82,000 IU (8.2 mg)/min intraarterially|nan|
|Drug: Norepinephrine 60, 120, 240 pmol/min intraarterially over 5 min/dose level (two times; pre-dose and +3.5 hrs)|nan|
|Drug: Acetylcholine 6.25, 12.5, 25 nmol/min intraarterially over 3 min/dose level (two times; pre-dose and +3.5 hrs)|nan|
|Drug: Glyceroltrinitrate (nitroglycerine) 4, 8, 16 nmol/min over 3 min/dose level (two times; pre-dose and +3.5 hrs)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forearm blood flow responses to acetylcholine, nitroglycerine and norepinephrine (ratio between intervention and control arm) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Markers of inflammation and oxidative stress, change in MAP, change in pulse rate, subjective symptoms and body temperature; antibodies against rhSOD |  |  |