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| Sponsors and Collaborators: |
Vanderbilt University National Center for Research Resources (NCRR) |
|---|---|
| Information provided by: | Vanderbilt University |
| ClinicalTrials.gov Identifier: | NCT00515021 |
Purpose
To determine if nighttime administration of an aldosterone antagonist would effectively lower peak plasma PAI-1 levels more effectively than morning administration.
| Condition | Intervention | Phase |
|---|---|---|
|
Metabolic Syndrome X |
Drug: Eplerenone (Morning vs. evening drug regimen) |
Phase IV |
| Study Type: | Interventional |
| Study Design: | Supportive Care, Randomized, Double Blind (Subject, Investigator), Active Control, Crossover Assignment, Efficacy Study |
| Official Title: | The Effects of Night-Time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1 |
| Estimated Enrollment: | 40 |
| Study Start Date: | April 2007 |
| Estimated Study Completion Date: | April 2010 |
| Estimated Primary Completion Date: | April 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
1: Experimental
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 vs. evening drug regimen)
Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks or 50mg, by mouth, daily, in the evening x 2 weeks 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. |
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 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 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.
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Metabolic Syndrome (3 or more of the following):
Exclusion Criteria:
Contacts and Locations| United States, Tennessee | |
| Vanderbilt University Medical Center | |
| Nashville, Tennessee, United States, 37232-8802 | |
| Principal Investigator: | James A Muldowney, III, MD | Vanderbilt University |
More Information
| Responsible Party: | Vanderbilt University School of Medicine ( James A. S. Muldowney III, M.D., Principal Investigator ) |
| Study ID Numbers: | 070183 |
| Study First Received: | August 9, 2007 |
| Last Updated: | January 27, 2009 |
| ClinicalTrials.gov Identifier: | NCT00515021 History of Changes |
| Health Authority: | United States: Institutional Review Board |
|
Metabolic syndrome Aldosterone inhibitor Diurnal drug regimen PAI-1 levels |
|
Serine Proteinase Inhibitors Metabolic Syndrome X Metabolic Diseases Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Fibrinolytic Agents Cardiovascular Agents Hormones Protease Inhibitors Abdominal Obesity Metabolic Syndrome |
Hyperinsulinism Fibrin Modulating Agents Eplerenone Aldosterone Antagonists Plasminogen Activator Inhibitor 1 Insulin Resistance Glucose Metabolism Disorders Metabolic Disorder Plasminogen Plasminogen Inactivators |
|
Serine Proteinase Inhibitors Molecular Mechanisms of Pharmacological Action Hormone Antagonists Physiological Effects of Drugs Hematologic Agents Hormones, Hormone Substitutes, and Hormone Antagonists Fibrinolytic Agents Hyperinsulinism Fibrin Modulating Agents Pathologic Processes Syndrome Therapeutic Uses Plasminogen Activator Inhibitor 1 |
Plasminogen Plasminogen Inactivators Metabolic Diseases Disease Metabolic Syndrome X Enzyme Inhibitors Cardiovascular Agents Pharmacologic Actions Protease Inhibitors Eplerenone Aldosterone Antagonists Insulin Resistance Glucose Metabolism Disorders |
