L-Citrulline and Endothelial Function

Study Overview
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Brief Summary
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The effect of L-Citrulline is well studied in relation to muscle strength, exhaustion, exercise performance, and endothelial function in health and disease. This study will extend current body of knowledge and will investigate the effect of L-Citrulline on brain vascular function.

Detailed Description
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Endothelial function is associated with nitric oxide (NO) availability for vasodilation, blood pressure and blood flow regulation, and vascular health. A large body of evidence demonstrates that aging is associated with a decrease in bioavailability of NO, with more pronounced decrease in sedentary individuals. NO can be produced via the NO synthase (NOS) enzymes, which catalyze the conversion of L-Arginine - a semi-essential amino acid found in fish, nuts and legumes amongst others - to L-Citrulline and produce NO as an endproduct. While the effect of L-Citrulline is extensively studied in relation to muscle strength, exhaustion, exercise performance, as well as on endothelial function in healthy and diseased individuals (including obese and those with heart failure), the effect of L-Citrulline on brain vascular function is not well studied.

Official Title
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Effect of Oral L-Citrulline on the Peripheral and Central Endothelial Function in Young and Older Adults

Conditions
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Aging

Intervention / Treatment
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* Drug: L-Citrulline, 2500 mg capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21-45 and ≥55-90 years of age Adequate hearing and visual acuity to participate in the examinations Ability to read and write in English Competence to provide informed consent Exclusion Criteria: Active CNS disease including multiple sclerosis, uncontrolled seizures, active brain cancer Cerebrovascular accident other than TIA within 60 days prior to Visit 0 Major psychiatric disease, including major depression not currently controlled on medications, alcohol or drug abuse Treatment with other Citrulline enhancers (L-Arginine, L-Citrulline Malate) within 4 weeks prior to Visit 0 Any other medical condition which, in the opinion of investigator, would render the patient inappropriate or too unstable to complete the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

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: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Open label single arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-Citrulline<br>L-Citrulline 10 g/day per os for 1 week | Drug: L-Citrulline, 2500 mg capsule<br>* 4 capsules per day to achieve 10g/daily dose for the duration of 1 week intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in neurovascular coupling using functional near infrared spectroscopy (fNIRS) | Functional near infrared spectroscopy (fNIRS) will be performed during the cognitive n-back task. fNIRS approach generates data that represent a relative change in oxygenated and deoxygenated hemoglobin measured over the cortical brain tissues. Neurovascular coupling will be evaluated as a change in oxy- and deoxy-hemoglobin between before and after treatment. Units of measure - beta. Reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in neurovascular coupling using the dynamic retinal vessel analysis | Flicker light-induced dilation of the retinal vessels (percentage increase over baseline diameter) will be measured in the right or left eye of each study participant using the Dynamic Vessel Analyzer (DVA, IMEDOS Systems, Jena, Germany). Units of measure mm, reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in neuronal activity | EEG signal will be collected to generate spectral data. These data will be used for comparison of EEG activity between before and after treatment. Units of measure - power spectral density. Reported as a %change from baseline, before and after treatment. | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in microvascular endothelial function | Changes in microvascular endothelial function will be assessed using laser speckle contrast imaging (LSCI) in the hand using the flow mediated dilation approach. The change in skin perfusion is calculated and reported as a %change from baseline, between before and after treatment. Units of measure - perfusion index (arbitrary units). Reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in macrovascular endothelial function | Changes in macrovascular endothelial function will be assessed using sonography during flow mediated dilation approach. The change in brachial artery diameter (mm) is calculated and reported as a %change from baseline, between before and after treatment. | 1 week | 
| Change in Glycocalyx - perfused boundary region | Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include perfused boundary region (um), and will be used for comparison before and after treatment. | 1 week | 
| Change in capillary density | Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include capillary density (mm/mm^2), and will be used for comparison before and after treatment. | 1 week | 
| Change in red blood cell velocity | Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include red blood cell velocity (um/sec), and will be used for comparison before and after treatment. | 1 week | 
| Change in grip strength | The change in hand grip strength will be measured before and after intervention. Data collected will include measurements of power in kg for left and right hand respectively | 1 week | 
| Change in Attention | CANTAB research attention test.Reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in Working Memory | CANTAB research working memory test.Reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in Executive Function | CANTAB research executive function test.Reported as a %change from baseline, before and after treatment. | 1 week | 
| Change in Processing Speed | CANTAB research processing speed test.Reported as a %change from baseline, before and after treatment. | 1 week | 
| Blood collection | Blood samples will be collected to measure L-Citrullin related metabolites. | 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L-Citrulline