The Effect of Arginine and Citrulline Supplementation on Endothelial Dysfunction in Mitochondrial Diseases

Mitochondrial diseases occur due to inadequate energy production. In addition, nitric oxide (NO) deficiency occurs in mitochondrial diseases. The endothelial layer of blood vessels functions in maintaining blood vessels patency through producing NO which relaxes vascular smooth muscles and therefore maintains the patency of blood vessels and adequate blood perfusion. In mitochondrial diseases, endothelial cells fail to perform their normal function in maintaining the patency of blood vessels (endothelial dysfunction) because of the inability to produce enough NO. Endothelial dysfunction results in decreased blood perfusion in different organs which can contribute to the complications seen in mitochondrial diseases. The amino acids arginine and citrulline act as NO precursors and can increase NO production. In this study we hypothesize that due to the inability to produce enough NO patients with mitochondrial diseases have endothelial dysfunction that will improve after arginine or citrulline supplementation. The investigators will assess endothelial function using peripheral arterial tonometry before and after arginine or citrulline supplementation. The investigators expect that arginine and citrulline supplementation will improve endothelium function. This will support the therapeutic use of arginine and citrulline in mitochondrial diseases.

Study Overview

• Status: Completed
• Conditions: Mitochondrial Diseases
• Intervention / Treatment: Dietary supplement: Arginine; Dietary supplement: Citrulline

Detailed Description

The investigators will study 10 children with mitochondrial diseases and 10 healthy control children. The investigators will study control children to be able compare the results of children with mitochondrial diseases to control healthy children. Therefore, the investigators will study control children only once to compare these results to the results of children with mitochondrial diseases at baseline. To assess the effect of arginine and citrulline on children with mitochondrial diseases, the investigators need to assess children with mitochondrial diseases four times. First time as baseline. Then children with mitochondrial diseases will be randomized to receive either oral arginine or citrulline at a dose of 500 mg/kg/day divided in 3 doses daily for 2 weeks after which a second assessment will be performed. Oral arginine or citrulline will be discontinued and after a two-week washout period another baseline assessment will be done. After that, the child will be started on oral citrulline (if the participant received arginine the first time) or arginine (if the participant received citrulline the first time) at a dose of 500 mg/kg/day divided in 3 doses daily for 2 weeks after which a fourth assessment will be done.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Arab Emirates
  • Al Ain, United Arab Emirates
    • Tawam Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 14 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of mitochondrial disease with multi-organ disease involving neurological and/or muscular systems.
2. The diagnosis must be confirmed either molecularly (identifying mutations known to be associated with mitochondrial diseases) or by respiratory chain assay abnormalities.

Exclusion Criteria:

1. Have acute illness or physical disability interfering with ability to undergo the study procedures.
2. Known to have other factors that are known to result in endothelial dysfunction including hypertension, hyperlipidemia, and diabetes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arginine; Endothelial function will be assessed before and after arginine supplementation	Dietary supplement: Arginine; Arginine is an amino acids
Active Comparator: Citrulline; Endothelial function will be assessed before and after citrulline supplementation	Dietary supplement: Citrulline; Citrulline is an amino acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reactive hyperemic index (RHI)	Reactive hyperemic index (RHI) which reflects endothelial function will be measured using the EndoPAT instrument	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration levels of arginine and citrulline	Plasma arginine and citrulline levels will also be measured	2 year

Collaborators and Investigators

• Sponsor: Tawam Hospital
• Investigators: Principal Investigator: Ayman W El-Hattab, MD, Tawam Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: June 15, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimate): June 22, 2016

Study Record Updates

• Last Update Posted (Actual): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 17, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Mitochondrial Diseases
• Other Study ID Numbers: CED 343-14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes