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Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01595516
Recruitment Status : Completed
First Posted : May 10, 2012
Results First Posted : June 25, 2019
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Christopher DeSouza, University of Colorado, Boulder

Brief Summary:
The investigators hypothesize that nebivolol will improve endothelial t-PA release in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo. The investigators further hypothesize that the improvement in the capacity of the vascular endothelium to release t-PA with nebivolol is mediated, in part, by the compound's antioxidant properties.

Condition or disease Intervention/treatment Phase
Prehypertension Hypertension Drug: Nebivolol Drug: Metoprolol Drug: Placebo Other: Bradykinin Other: Saline Other: Vitamin C Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Nebivolol and Endothelial Regulation of Fibrinolysis
Study Start Date : February 2012
Actual Primary Completion Date : October 2017
Actual Study Completion Date : October 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Nebivolol Drug: Nebivolol
5 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Bystolic

Active Comparator: Metoprolol Drug: Metoprolol
100 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Toprol-XL

Placebo Comparator: Placebo Drug: Placebo
Gelatin capsule to be taken by mouth once per day for 12 weeks

Bradykinin Drug: Nebivolol
5 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Bystolic

Drug: Metoprolol
100 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Toprol-XL

Drug: Placebo
Gelatin capsule to be taken by mouth once per day for 12 weeks

Other: Bradykinin
Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.
Other Name: BDK

Saline Drug: Nebivolol
5 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Bystolic

Drug: Metoprolol
100 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Toprol-XL

Drug: Placebo
Gelatin capsule to be taken by mouth once per day for 12 weeks

Other: Bradykinin
Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.
Other Name: BDK

Other: Saline
Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured.

Other: Vitamin C
The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time (~20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured.

Vitamin C Drug: Nebivolol
5 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Bystolic

Drug: Metoprolol
100 mg tablet to be taken by mouth once per day for 12 weeks
Other Name: Toprol-XL

Other: Bradykinin
Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.
Other Name: BDK

Other: Saline
Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured.

Other: Vitamin C
The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time (~20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured.




Primary Outcome Measures :
  1. Heart Rate [ Time Frame: Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. ]
    Resting heart rate in the seated position

  2. Systolic Blood Pressure [ Time Frame: Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. ]
  3. Diastolic Blood Pressure [ Time Frame: Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. ]
  4. Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention [ Time Frame: t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. ]
    Net endothelial release of t-PA antigen in response to bradykinin (BDK) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK). t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.

  5. Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. [ Time Frame: t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. ]
    Net endothelial release of t-PA antigen in response to bradykinin (BDK) and bradykinin+vitamin C (BDK+C) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.

  6. Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. [ Time Frame: t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. ]
    Net endothelial release of t-PA antigen in response to BDK and BDK+C was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.



Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years.
  • Subjects will be prehypertensive/hypertensive defined as resting systolic blood pressure >125 mmHg and <160 mmHg and/or diastolic >80 mmHg and <100 mmHg.
  • All of the women in the study will be postmenopausal and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period.
  • Candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 1 year prior to the study.

Exclusion Criteria:

  • Candidates who smoke (currently or in the past 7 years), report more than low-risk alcohol consumption as defined as no more than 14 standard drinks/wk and no more than 4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces of 80-proof distilled spirits).
  • Potential candidates who are taking cardiovascular-acting (i.e. statins, blood pressure medication and aspirin) medications will not be eligible.
  • Fasting plasma glucose >126 mg/dL.
  • Potential candidates with a resting heart rate of < 50 beats/minute will be excluded.
  • Use of hormone replacement therapy.
  • In hypertensive subjects, a seated systolic blood pressure >160 mmHg or a seated diastolic blood pressure >100 mmHg will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01595516


Locations
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United States, Colorado
UC-Boulder Clinical and Translational Research Center
Boulder, Colorado, United States, 80309
Sponsors and Collaborators
University of Colorado, Boulder
Forest Laboratories
Investigators
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Principal Investigator: Christopher DeSouza, Ph.D. University of Colorado at Boulder
  Study Documents (Full-Text)

Documents provided by Christopher DeSouza, University of Colorado, Boulder:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Christopher DeSouza, Professor, University of Colorado, Boulder
ClinicalTrials.gov Identifier: NCT01595516    
Other Study ID Numbers: BYS-MD-72
First Posted: May 10, 2012    Key Record Dates
Results First Posted: June 25, 2019
Last Update Posted: June 25, 2019
Last Verified: June 2019
Additional relevant MeSH terms:
Layout table for MeSH terms
Prehypertension
Vascular Diseases
Cardiovascular Diseases
Ascorbic Acid
Metoprolol
Nebivolol
Bradykinin
Kininogens
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Vasodilator Agents
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists