Impact of NOS, COX, and ROS Inhibition on Cerebral Blood Flow Regulation

NCT03066115 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 2016-1014
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Elucidating cerebrovascular control mechanisms during physiologic stress may help identify novel therapeutic targets aimed at preventing or reducing the impact of cerebrovascular disease. The physiological stressors of hypoxia and hypercapnia will be utilized to elicit increases in cerebral blood flow (CBF), and intravenously infused drugs will allow for the testing of potential mechanisms of cerebrovascular control. Specifically, the contributions of nitric oxide synthase (NOS), cyclooxygenase (COX), and reactive oxygen species (ROS) to hypoxic and hypercapnic increases in CBF will be examined. The concept that these mechanisms interact in a compensatory fashion to ensure adequate CBF during both hypoxia and hypercapnia will also be tested. \~25 young, healthy men and women will be tested at rest and during hypoxia and hypercapnia. Subjects will participate in two randomized, counterbalanced study visits under the following conditions: inhibition of NOS, NOS-COX, and NOS-COX-ROS or inhibition of COX, COX-NOS, COX-NOS-ROS. During hypoxia, arterial oxygen saturation will be lowered to 80% and end-tidal carbon dioxide will be maintained at basal levels. During hypercapnia arterial carbon dioxide will be increased \~10 mmHg above basal levels and arterial oxygen saturation will be maintained. Blood flow velocity will be measured with transcranial Doppler ultrasound in the anterior (middle cerebral artery; MCA) and posterior (basilar artery; BA) circulations as a surrogate for CBF. It is hypothesized that both NOS and COX independently contribute to hypoxic and hypercapnic vasodilation in the MCA and BA, combined NOS-COX contribute to hypoxic and hypercapnic vasodilation in MCA and BA to a greater extent than either NOS or COX alone, and NOS-COX-ROS contribute to hypoxic and hypercapnic vasodilation in the MCA and BA to a greater extent than NOS-COX.

Conditions

Hypoxia; Hypercapnia

Keywords

Cerebral blood flow; Cyclooxygenase; Nitric oxide synthase; Reactive Oxygen Species

Outcome Measures

Primary Outcomes (1)

• Change in cerebral blood flow velocity in the middle cerebral artery

  How cerebral blood flow velocity changes during hypoxia or hypercapnia with COX, NOS, and ROS inhibition in the middle cerebral artery as measured by transcranial Doppler ultrasound.

  Through study completion (up to 1 year)

Secondary Outcomes (1)

• Change in cerebral blood flow velocity in the basilar artery

  Through study completion (up to 1 year)

Study Arms (2)

NOS, COX, and ROS Inhibition

EXPERIMENTAL

Subjects will receive L-NMMA, ketorolac, then ascorbic acid via intravenous catheter. L-NMMA will have a 3 mg kg-1 loading dose over 5-minutes (36 mg kg-1 hr-1), followed by a maintenance dose of 1 mg kg-1 hr-1. Ketorolac will have a 0.3 mg kg-1 loading dose over 5 minutes (3.6 mg kg-1 hr-1) with a minimum loading dose of 15 mg. This will be followed by a maintenance dose of 0.03 mg kg-1 hr-1. Ascorbic acid will have a loading dose of 0.035 g kg fat-free mass-1 over 5-minutes (0.42 g kg fat-free mass-1 hr-1), followed by a maintenance dose of 0.060 g kg fat-free mass-1 hr-1. Cerebral blood flow velocity will be measured throughout the drug infusions via transcranial Doppler ultrasound.

Drug: L-NMMA; Drug: Ketorolac; Drug: Ascorbic Acid; Procedure: Intravenous Catheter; Procedure: Transcranial Doppler Ultrasound

COX, NOS, and ROS Inhibition

EXPERIMENTAL

Subjects will receive ketorolac, L-NMMA, then ascorbic acid via intravenous catheter. Ketorolac will have a 0.3 mg kg-1 loading dose over 5 minutes (3.6 mg kg-1 hr-1) with a minimum loading dose of 15 mg. This will be followed by a maintenance dose of 0.03 mg kg-1 hr-1. L-NMMA will have a 3 mg kg-1 loading dose over 5-minutes (36 mg kg-1 hr-1), followed by a maintenance dose of 1 mg kg-1 hr-1. Ascorbic acid will have a loading dose of 0.035 g kg fat-free mass-1 over 5-minutes (0.42 g kg fat-free mass-1 hr-1), followed by a maintenance dose of 0.060 g kg fat-free mass-1 hr-1. Cerebral blood flow velocity will be measured throughout the drug infusions via transcranial Doppler ultrasound.

Drug: L-NMMA; Drug: Ketorolac; Drug: Ascorbic Acid; Procedure: Intravenous Catheter; Procedure: Transcranial Doppler Ultrasound

Interventions

L-NMMA DRUG

See arm description.

Also known as: NOS Inhibition

COX, NOS, and ROS Inhibition; NOS, COX, and ROS Inhibition

Ketorolac DRUG

See arm description.

Also known as: COX Inhibition

COX, NOS, and ROS Inhibition; NOS, COX, and ROS Inhibition

Ascorbic Acid DRUG

See arm description.

Also known as: ROS Inhibition

COX, NOS, and ROS Inhibition; NOS, COX, and ROS Inhibition

Intravenous Catheter PROCEDURE

Two intravenous catheters will be placed for each study visit. One catheter will be used for the intravenous infusion of study drugs (L-NMMA, Ketorolac, and Ascorbic Acid). The second catheter will be used to draw intermittent blood samples at 8-specific time points throughout each study visit to ensure pharmaceutical efficacy and examine systemic physiologic blood variables of interest.

Also known as: Cath

COX, NOS, and ROS Inhibition; NOS, COX, and ROS Inhibition

Transcranial Doppler Ultrasound PROCEDURE

MCAv will be measured via the transtemporal window while BAv will be measured through the transforaminal window with 2-MHz transcranial Doppler ultrasound probes (TCD, Neurovision model 500M, Multigon Industries, Inc.; Yonkers, NY, USA)

Also known as: Ultrasound

COX, NOS, and ROS Inhibition; NOS, COX, and ROS Inhibition

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: 18 ≤ years ≤ 45
• Free of disease and otherwise healthy as determined by health history questionnaire
• Not currently taking medication with the exception of birth control as determined by health history questionnaire
• Low to moderate physical activity will be permitted and assessed by a physical activity questionnaire (≤ 4 hours of physical activity/week)
• Body mass index (BMI) \< 25 kg/m2
• Resting blood pressure \<140/\<90 mmHg (lowest of three measures)
• Resting heart rate \<100 bpm
• Resting pulse oximetry oxygen saturation (SPO2) \>95%
• Fasting venous blood values (average of two measures)
• Glucose \<100 mg/dL
• Creatinine \< 1.5 mg/dL
• Total cholesterol \<200 mg/dL
• i. HDL cholesterol \>40 mg/dL (men) ii. HDL cholesterol \>50 mg/dL (women) iii. LDL cholesterol \< 130 mg/dL d. Triglycerides \<150 mg/dL
• Subjects must be willing to report to the laboratory on all study days after completing
• Minimum 10-hour fast

You may not qualify if:

• Coronary artery disease
• Stroke
• Heart attack
• Heart valve disease
• Congestive heart failure
• Previous heart surgery
• Lung disease
• Peripheral vascular disease
• Gastrointestinal (GI) bleeding
• Allergy or Intolerance to Aspirin or NSAIDS
• History of renal/kidney disease, insufficiency, or injury
• Smoke or use tobacco within the last year
• Subject has an abnormality or contraindication to study participation, which is not covered in the eligibility criteria.
• Additionally, women will be excluded if they are
• Pregnant (as determined by a urine pregnancy test on screening and study days)

Sponsors & Collaborators

• University of Wisconsin, Madison: lead

Study Sites (1)

University of Wisconsin, Madison

Madison, Wisconsin, 53706, United States

Location

MeSH Terms

Conditions

Hypoxia; Hypercapnia

Interventions

omega-N-Methylarginine; Ketorolac; Ascorbic Acid; Ultrasonography, Doppler, Transcranial; High-Energy Shock Waves

Condition Hierarchy (Ancestors)

Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Indomethacin; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Echoencephalography; Neuroradiography; Neuroimaging; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Radiography; Ultrasonography; Ultrasonography, Doppler; Diagnostic Techniques, Neurological; Investigative Techniques; Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena

Study Officials

• William G Schrage, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2017
• First Posted: February 28, 2017
• Study Start: December 1, 2020
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: January 10, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)