Arginase Inhibition in Humans With Obesity

Arginase Inhibition and Endothelial Function in Humans With Obesity

To evaluate the efficacy of arginase inhibition on endothelial function in humans with obesity.

Study Overview

• Status: Completed
• Conditions: Obese; Endothelial Function
• Intervention / Treatment: Drug: Nω-hydroxy-nor-arginine

Detailed Description

The study is performed on one group of subjects with body mass index >35 and the absence of type 2 diabetes.

Inclusion criteria:

Body mass index >35 kg/m2.

Exclusion criteria:

Age >80 years. Type 2 diabetes defined as >7 mmol/L in fasting plasma glucose or >11 mmol/L following 2h of oral glycemic load.

Myocardial infarction/unstable angina within 6 weeks prior to the study. Treatment with oral anticoagulants (Warfarin or New oral anticoagulants), Raynaud's phenomenon, peripheral vasculopathies, arterial shunting or other vascular surgery of the study arm.

Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol.

Participant in an ongoing study. Unwillingness to participate following oral and written information.

Forearm blood flow is determined by venous occlusion plethysmography. Endothelium-dependent vasodilatation is determined during intra-brachial artery infusion of serotonin (21, 70 and 210 ng/min). Endothelium-independent vasodilatation is determined by infusion of sodium nitroprusside (SNP; 1, 3 and 10 µg/min). Each dose is given for 2 min at a rate of 2.5 ml/min. Data are expressed as percentage change in forearm blood from baseline flow.

Fifteen subjects are included. On the day of the study the subject arrives to the laboratory after having a light breakfast. Forearm vessels of the non-dominant arm are cannulated and forearm blood flow is determined as described above. Baseline endothelium-dependent and endothelium-independent vasodilatation is determined by intra-arterial infusions of serotonin and SNP, respectively. Thereafter an intra-arterial infusion of the arginase inhibitor N-omega-hydroxy-nor-l-arginine (nor-NOHA) is administered as an intra-arterial infusion at a rate of 0.1 mg/min and is maintained for 120 min. The dose is based on a previous study by our group demonstrating improved endothelial function. Endothelium-dependent and -independent vasodilatation is reassessed at 120 min of infusion.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 17176
    • Karolinska Institutet, Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

BMI >35kg/m2

Exclusion Criteria:

Age >80 years. Type 2 diabetes defined as >7 mmol/L in fasting plasma glucose or >11 mmol/L following 2h of oral glycemic load.

Myocardial infarction/unstable angina within 6 weeks prior to the study. Treatment with oral anticoagulants (Warfarin or New oral anticoagulants), Raynaud's phenomenon, peripheral vasculopathies, arterial shunting or other vascular surgery of the study arm.

Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol.

Participant in an ongoing study. Unwillingness to participate following oral and written information.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arginase inhibition; Endothelium dependent and -independent vasodilatation before and after 120min intra-arterial administration of arginase the inhibitor N-omega-hydroxy-nor-l-arginine (nor-NOHA) is started and is maintained for 120 min at a rate of 0.1 mg/min	Drug: Nω-hydroxy-nor-arginine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelium-dependent change in forearm blood flow	Percentage change in forearm blood flow from baseline induced by the endothelium-dependent vasodilator serotonin during arginase blockade vs. saline.	120 min intraarterial infusion of the arginase inhibitor nor-NOHA

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelium-independent change in forearm blood flow	Percentage change in forearm blood flow from baseline induced by the endothelium-independent vasodilator nitroprusside during arginase blockade vs. saline.	120 min intraarterial infusion of the arginase inhibitor nor-NOHA

Collaborators and Investigators

• Sponsor: Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): September 1, 2021
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: August 21, 2022
• First Submitted That Met QC Criteria: September 7, 2022
• First Posted (Actual): September 13, 2022

Study Record Updates

• Last Update Posted (Actual): September 13, 2022
• Last Update Submitted That Met QC Criteria: September 7, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity
• Other Study ID Numbers: 2016/1173-32

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No