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Diurnal Variation of Plasminogen Activator Inhibitor-1

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ClinicalTrials.gov Identifier: NCT00515021
Recruitment Status : Completed
First Posted : August 13, 2007
Results First Posted : February 1, 2019
Last Update Posted : February 1, 2019
Sponsor:
Collaborator:
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
James Muldowney, Vanderbilt University Medical Center

Study Description
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Brief Summary:
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma Plasminogen Activator Inhibitor-1 (PAI-1) levels more effectively than morning administration.

Condition or disease Intervention/treatment Phase
Metabolic Syndrome X Drug: Eplerenone (Morning) Drug: Eplerenone (Night-time) Phase 4

Detailed Description:

Plasminogen activator inhibitor-1, a member of the serine protease inhibitor (serpin) superfamily, is the principal inhibitor to tissue-type plasminogen activator and urokinase-type plasminogen activator. Elevated plasma PAI-1 levels, an independent cardiovascular risk factor, has been shown to be a predictor of recurrent myocardial infarction (MI). Acute changes in plasma PAI-1 after MI is a predictor of mortality. PAI-1 levels are elevated in the individuals with hypertension, insulin resistance, hypertriglyceridemia, obesity, and the constellation of risk-factors known as the metabolic syndrome. PAI-1 is synthesized in the liver, vascular endothelium, vascular smooth muscle, and visceral adipose tissue. A number of factors have been shown to regulate PAI-1, including metabolic factors such as insulin, glucose, triglycerides; inflammatory cytokines such as tumor necrosis factor-α, transforming growth factor-β, interleukin-1, and more notably, components of the renin-angiotensin-aldosterone system (RAAS), namely angiotensin II and aldosterone.

PAI-1 also has a diurnal variation with a peak plasma level occurring between 8 and 9 AM that may help explain why the incidence of acute MI is highest in the morning and why thrombolysis is least effective at that time. PAI-1's diurnal variation is been shown to be directly regulated by central and peripheral circadian pacemakers in vitro, and in vivo. Our group has observed that the diurnal variation of plasma PAI-1 levels is blunted and delayed in blind individuals who's circadian mechanisms are free running (not controlled by a central circadian pacemaker) when compared to those whose circadian rhythms are entrained (controlled by a central circadian pacemaker) (unpublished data), suggesting an additional system may modulate diurnal variation of PAI-1. As plasma renin activity (PRA) and aldosterone levels peak earlier than PAI-1 levels, they may be partially responsible. Indeed, continuous infusion of candesartan eliminated diurnal variation of aortic PAI-1 message expression in Wistar-Kyoto and spontaneously hypertensive rats, while hydralazine did not.

The use of therapies to modulate plasma PAI-1 levels in human subjects have met with variable success. Low salt diet was shown to increase plasma PAI-1 levels in normotensive subjects in a manner that correlated with plasma aldosterone levels. Twice daily treatment with quinapril (40mg) lowered plasma PAI-1 levels during the expected peak time. In a second study of twice daily quinapril compared to twice daily losartan in normotensive subjects both only had a modest effect on plasma PAI-1 levels. A third study helped to explain this finding. In a crossover study, hypertensive subjects received daily spironolactone or hydrochlorothiazide (HCTZ) in a randomized fashion. Plasma PAI-1 levels were increased after HCTZ treatment, but not significantly changed from baseline with spironolactone treatment. Spironolactone treatment, however, resulted in significantly higher aldosterone levels. The correlation between plasma aldosterone and PAI-1 that was observed at baseline and with HCTZ treatment was not observed in the spironolactone arm, suggesting that the endogenous relationship between aldosterone and PAI-1 can be disrupted by mineralocorticoid receptor antagonism.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: The Effects of Night-time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1
Study Start Date : April 2007
Actual Primary Completion Date : April 2010
Actual Study Completion Date : April 2010

Resource links provided by the National Library of Medicine

Drug Information available for: Eplerenone

Arms and Interventions
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Arm Intervention/treatment
Experimental: Daytime then nightime dosing
Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks.
 Drug: Eplerenone (Morning)

Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 4 weeks at 100mg.

100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 100mg, by mouth, daily, in the evening x another 4 weeks.

Other Name: Inspra

Drug: Eplerenone (Night-time)
Eplerenone - 50mg, by mouth, daily in the evening x 2 weeks followed by 4 weeks at 100mg
Other Name: Inspra
Experimental: Nighttime then daytime dosing
Eplerenone - 50mg, by mouth, daily, in the evening x 2 weeks followed by 100mg, by mouth, daily, in the evening x 4 weeks then patients cross over to 50mg, by mouth, daily, in the morning x 2 weeks followed by 100mg, by mouth, daily, in the morning x 4 weeks.
 Drug: Eplerenone (Morning)

Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 4 weeks at 100mg.

100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 100mg, by mouth, daily, in the evening x another 4 weeks.

Other Name: Inspra

Drug: Eplerenone (Night-time)
Eplerenone - 50mg, by mouth, daily in the evening x 2 weeks followed by 4 weeks at 100mg
Other Name: Inspra


Outcome Measures
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Primary Outcome Measures :
  1. Plasminogen Activator Inhibitor-1 (PAI-1) Levels [ Time Frame: Baseline ]
    baseline PAI-1 levels prior to drug administration

  2. Plasminogen Activator Inhibitor-1 (PAI-1) Levels [ Time Frame: after 6 weeks on Eplerenone ]
    PAI-1 levels after Eplerenone 50mg daily for 2 weeks then 100mg daily for 4 weeks. Time of administration varied in the arms, either morning or night time dosing.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age18-65

  • Metabolic Syndrome (3 or more of the following):

    1. Blood pressure 130/85 or greater
    2. Central obesity (Waist - Male > 40", Female > 35")
    3. Fasting glucose ≥ 110 mg/dl
    4. Low HDL (Male < 40 mg/dl, Female < 50 mg/dl)
    5. Elevated Triglycerides (> 150 mg/dl)

Exclusion Criteria:

  • Cigarette Use
  • Renal insufficiency
  • Coronary Artery Disease
  • Diabetes
  • Blindness
  • Cerebrovascular Disease
  • Secondary hypertension (renal artery stenosis, pheo, etc.)
  • RAAS disease (Primary Aldosteronism, etc.)
  • Other chronic illness (cancer, autoimmune or liver disease)
  • Pregnancy
  • Anemia (Hgb < 12 mg/dl)
  • Evening or Night Shift work
  • Transmeridian travel in previous 6 months
  • History of sleep disorders
  • Hypokalemia (serum potassium < 3.5 milliequivalent (mEq/L)
  • Hyperkalemia (serum potassium > 5.5 mEq/L
  • Reported hypersensitivity to HCTZ or eplerenone
Contacts and Locations
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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): NCT00515021


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232-8802
Sponsors and Collaborators
Vanderbilt University Medical Center
National Center for Research Resources (NCRR)
Investigators
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Principal Investigator: James A Muldowney, III, MD Vanderbilt University
More Information
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Responsible Party: James Muldowney, Assistant Professor, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT00515021    
Other Study ID Numbers: 070183
First Posted: August 13, 2007    Key Record Dates
Results First Posted: February 1, 2019
Last Update Posted: February 1, 2019
Last Verified: January 2019
Keywords provided by James Muldowney, Vanderbilt University Medical Center:
Metabolic syndrome
Aldosterone inhibitor
Diurnal drug regimen
PAI-1 levels
Additional relevant MeSH terms:
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Metabolic Syndrome
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Eplerenone
Mineralocorticoid Receptor Antagonists
 Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Antihypertensive Agents