Ignite Creation Date:
2024-05-05 @ 10:58 PM
Last Modification Date:
2024-10-26 @ 10:26 AM
Study NCT ID:
NCT01228214
Status:
UNKNOWN
Last Update Posted:
2013-03-19
First Post:
2010-10-25
Brief Title:
Novel Treatment for Coronary Artery Disease
Sponsor:
University of Carabobo
Organization:
University of Carabobo
Study Overview
Official Title:
Randomized Double-Blind Placebo-Controlled Study of Pyrazinoylguanidine Hydrochloride Amiloride in Subjects With Coronary Artery Disease
Status:
UNKNOWN
Status Verified Date:
2013-03
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Treatment of coronary artery disease is a major health care problem across the entire word and the United States Unfortunately despite a number of medical advances diagnostic procedure or epidemiological studies the treatment of these patients remain complex and and at times frustrating In fact the COURAGE trial conducted in 50 centers across United States and Canada documented that drug treatment coronary interventions or both were not effective solution in coronary artery diseases
A novel approach has recently been developed based on the critical role of the potassium K content in red-blood-cell in myocardial oxygenation since oxygen and K binding by hemoglobin red-blood-cell occurs simultaneously in blood passing through the lungs whereas in the organs as the heart the hemoglobin release both Oxygen and K ions
This apparently simple mechanisms occurs in human blood in all individuals but could be altered in subjects with acquired or hereditable defect in red-blood-cell K content as in hypertensives or CAD patients
A novel approach has recently been developed based on the critical role of the potassium K content in red-blood-cell in myocardial oxygenation since oxygen and K binding by hemoglobin red-blood-cell occurs simultaneously in blood passing through the lungs whereas in the organs as the heart the hemoglobin release both Oxygen and K ions
This apparently simple mechanisms occurs in human blood in all individuals but could be altered in subjects with acquired or hereditable defect in red-blood-cell K content as in hypertensives or CAD patients
Detailed Description:
Treatment of Cardiovascular Diseases CVD is a major health care problem across the entire word and particularly in the United States In fact these life-threatening disorders are a major cause of emergency medical care and hospitalization in the United States and according the National Center for Health Statistics NCHS there were approximately 1565000 hospitalizations for primary or secondary diagnosis of an acute coronary syndrome ACS 669000 for unstable angina UA and 896000 for myocardial infarction MI In the 2003 NCHS reported 4497000 visits to emergency departments for primary diagnosis of CVD wherein the average age of a person having a first heart attack is calculated at 658 years for men and 704 years for women
Further studies provided by the Heart Disease and Stroke Statistics-2007 Update of the American Heart Association reported an estimated 79 400 000 American adults 1 in 3 have 1 or more types of CVD Of these and 37 500 000 are estimated to be age 65 or older As a separate diagnosis high blood pressure or hypertension accounts for approximately 72 000 000 of patients defined as systolic pressure 140 mm Hg or greater andor diastolic pressure 90 mm Hg or greater taking antihypertensive medication coronary heart disease CHD for approximately 15 800 000 patients myocardial infarction for approximately 7 900 000 patients and angina pectoris chest pain secondary to ischemic heart disease for approximately 8 900 000 patients
Although the treatment of angina chest pain secondary to ischemic heart disease and one of the most common and early symptom of coronary artery disease can be tracked as far as 1880s it still represents a medically unresolved problem Indeed treatment of angina in particular as well as associated condition as ACS UA and MI involves a large number of life-style change recommendations dietetic advice drugs coronary artery intervention or coronary bypass surgery aimed to improve symptoms quality of life of patients and even primary or secondary prevention of the CVD Unfortunately despite a century of medical advances and epidemiological studies the current approach to CVD and coronary artery disease remain complex and at times frustrating
Among some of the proposals to combat CVD have included the single polypillaspirin statin 3 blood pressure lowering agents in half dose and folic acid as a strategy to reduce CVD by more than 80 remains presently unresolved regression of coronary atherosclerosis by using Simvastatin and intravascular ultrasound study was determined to be unpractical It remains to be determined whether these changes will translate to meaningful reductions in clinical events or whether new antithrombotic agents for these CVD patients can provide an adequate solution However the overarching determination in view of the purported successes to date remains whether these results in highly selected patient populations can be matched to the real-world treatment of acute coronary syndromes
In a recent study called the COURAGE Trial Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation conducted in 50 hospital centers across the United States and Canada showed that optimal drug treatment with percutaneous coronary interventions PCI for stable coronary artery disease was not more effective than optimal medical therapy alone for preventing cardiovascular events hospitalization or death suggesting that drugs surgical procedures or both were not a statistically effective solution for CHD
For more than a century hemodynamic mechanisms involving the coupled tissue O2CO2 gas exchange and ion HK transport by Hemoglobin Hb in red blood cells RBC have been well known to the scientific community and has been termed the so-called BohrHaldane Effect Data to date has been shown that the RBC has a number of critical roles in maintaining normal vascular function blood flow tissue oxygenation and acid-base regulation These critical roles including the nitric oxygen NO transport NO synthetase expression platelet aggregation vascular rheology and endothelial function have been the subject of extensive studies by many investigators Unfortunately and despite such multiple integrated functions to maintain tissue oxygenation in health and diseases states the role of RBC has never been of interest in the therapeutic approach of patients with CHD specially the ischemic condition of ACS UA or MI
In this context the evidence from our laboratory that erythrocytes have a critical role in body K homeostasis along with the finding of a hereditable defect in erythrocyte K uptake in hypertensives and 46 of their normotensive adolescents young adults offspring led us to assess whether a defective K uptake could impair the regulation of HK exchange and oxygen delivery in CAD Since then a Patent Application whose filed in the USPTOand a simple medical device for intracellular K measurement in red blood cell by miniature K and Na ion-selective electrode was proposed in conjunction with the University of Michigan
Although many drugs were tested in order to improve or correct the defective red cell K transport the most promising compound was the 35-diamino-6-chloro-N- diaminomethylenepyrazinecarboxamide dihydrate derivative amiloride hydrochloride recently published as a new drug patent application
The drug originally tested in hypertensives with low RBC K uptake independently of cell Na content dietary intake or drugs became an effective and predictable method to improve RBC K homeostasis that is critically related to other red-cell functions such as the pH regulation and oxygen delivery More important the observation that reversal of the abnormal RBC K content was associated with a decline and better control of BP fasting plasma glucose and regression of ST-T alteration related to LVH or CHD led us to evaluate the role of RBC in the mechanism of HK exchange tissue oxygenation in health and disease states
This Clinical Trial will address the effects of Amiloride in RBC K uptake and consequently the simultaneous tissue HK and O2CO2 exchange its therapeutic effect on BP control and possible improvement on Angina Duke Treadmill Score and ST-T alteration of LVH or CAD
METHODS OF TREATMENT
Each patient will be prospectively evaluated in order to assess the effects of Amiloride on reversion of angina and ECG alterations of ischemia in CAD After written consent the subject will enter the Double-Blind trial of Amiloride Vs Placebo along whit the optimal treatment for Angina and CHD Amiloride 5 to 10 mg will be given daily before breakfast while other medication for angina and associated diseases as hypertension or diabetes were continued Each patient will be clinically evaluated for angina dyspnea or arrhythmias at 1-week 1 3 6 months period Serial ECG Ion Transport Studies BIA non-invasive hemodynamic and clinical biochemistry will be obtained at 1 3 6 months follow-up period Echocardiograms were obtained basal and 6- months period In this trial each subject with plasma ionized calcium 10 mmoll will received 1g of Ca- gluconolactate until the level was 10 mmoll
Following the first 3-month trial patients with reversion of angina and improvement of ECG abnormalities of ischemia will have low doses of amiloride 5 to 75 mg while nitrates B-blockers or Calcium Channel Blockers will be progressively discontinued if no evidence of angina occurred and if no new no ECG ST-T alteration of ischemia developed Therefore amiloride withwithout aspirin Statins and medication for hypertension or diabetes will be the established treatment until the end of trial
Further studies provided by the Heart Disease and Stroke Statistics-2007 Update of the American Heart Association reported an estimated 79 400 000 American adults 1 in 3 have 1 or more types of CVD Of these and 37 500 000 are estimated to be age 65 or older As a separate diagnosis high blood pressure or hypertension accounts for approximately 72 000 000 of patients defined as systolic pressure 140 mm Hg or greater andor diastolic pressure 90 mm Hg or greater taking antihypertensive medication coronary heart disease CHD for approximately 15 800 000 patients myocardial infarction for approximately 7 900 000 patients and angina pectoris chest pain secondary to ischemic heart disease for approximately 8 900 000 patients
Although the treatment of angina chest pain secondary to ischemic heart disease and one of the most common and early symptom of coronary artery disease can be tracked as far as 1880s it still represents a medically unresolved problem Indeed treatment of angina in particular as well as associated condition as ACS UA and MI involves a large number of life-style change recommendations dietetic advice drugs coronary artery intervention or coronary bypass surgery aimed to improve symptoms quality of life of patients and even primary or secondary prevention of the CVD Unfortunately despite a century of medical advances and epidemiological studies the current approach to CVD and coronary artery disease remain complex and at times frustrating
Among some of the proposals to combat CVD have included the single polypillaspirin statin 3 blood pressure lowering agents in half dose and folic acid as a strategy to reduce CVD by more than 80 remains presently unresolved regression of coronary atherosclerosis by using Simvastatin and intravascular ultrasound study was determined to be unpractical It remains to be determined whether these changes will translate to meaningful reductions in clinical events or whether new antithrombotic agents for these CVD patients can provide an adequate solution However the overarching determination in view of the purported successes to date remains whether these results in highly selected patient populations can be matched to the real-world treatment of acute coronary syndromes
In a recent study called the COURAGE Trial Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation conducted in 50 hospital centers across the United States and Canada showed that optimal drug treatment with percutaneous coronary interventions PCI for stable coronary artery disease was not more effective than optimal medical therapy alone for preventing cardiovascular events hospitalization or death suggesting that drugs surgical procedures or both were not a statistically effective solution for CHD
For more than a century hemodynamic mechanisms involving the coupled tissue O2CO2 gas exchange and ion HK transport by Hemoglobin Hb in red blood cells RBC have been well known to the scientific community and has been termed the so-called BohrHaldane Effect Data to date has been shown that the RBC has a number of critical roles in maintaining normal vascular function blood flow tissue oxygenation and acid-base regulation These critical roles including the nitric oxygen NO transport NO synthetase expression platelet aggregation vascular rheology and endothelial function have been the subject of extensive studies by many investigators Unfortunately and despite such multiple integrated functions to maintain tissue oxygenation in health and diseases states the role of RBC has never been of interest in the therapeutic approach of patients with CHD specially the ischemic condition of ACS UA or MI
In this context the evidence from our laboratory that erythrocytes have a critical role in body K homeostasis along with the finding of a hereditable defect in erythrocyte K uptake in hypertensives and 46 of their normotensive adolescents young adults offspring led us to assess whether a defective K uptake could impair the regulation of HK exchange and oxygen delivery in CAD Since then a Patent Application whose filed in the USPTOand a simple medical device for intracellular K measurement in red blood cell by miniature K and Na ion-selective electrode was proposed in conjunction with the University of Michigan
Although many drugs were tested in order to improve or correct the defective red cell K transport the most promising compound was the 35-diamino-6-chloro-N- diaminomethylenepyrazinecarboxamide dihydrate derivative amiloride hydrochloride recently published as a new drug patent application
The drug originally tested in hypertensives with low RBC K uptake independently of cell Na content dietary intake or drugs became an effective and predictable method to improve RBC K homeostasis that is critically related to other red-cell functions such as the pH regulation and oxygen delivery More important the observation that reversal of the abnormal RBC K content was associated with a decline and better control of BP fasting plasma glucose and regression of ST-T alteration related to LVH or CHD led us to evaluate the role of RBC in the mechanism of HK exchange tissue oxygenation in health and disease states
This Clinical Trial will address the effects of Amiloride in RBC K uptake and consequently the simultaneous tissue HK and O2CO2 exchange its therapeutic effect on BP control and possible improvement on Angina Duke Treadmill Score and ST-T alteration of LVH or CAD
METHODS OF TREATMENT
Each patient will be prospectively evaluated in order to assess the effects of Amiloride on reversion of angina and ECG alterations of ischemia in CAD After written consent the subject will enter the Double-Blind trial of Amiloride Vs Placebo along whit the optimal treatment for Angina and CHD Amiloride 5 to 10 mg will be given daily before breakfast while other medication for angina and associated diseases as hypertension or diabetes were continued Each patient will be clinically evaluated for angina dyspnea or arrhythmias at 1-week 1 3 6 months period Serial ECG Ion Transport Studies BIA non-invasive hemodynamic and clinical biochemistry will be obtained at 1 3 6 months follow-up period Echocardiograms were obtained basal and 6- months period In this trial each subject with plasma ionized calcium 10 mmoll will received 1g of Ca- gluconolactate until the level was 10 mmoll
Following the first 3-month trial patients with reversion of angina and improvement of ECG abnormalities of ischemia will have low doses of amiloride 5 to 75 mg while nitrates B-blockers or Calcium Channel Blockers will be progressively discontinued if no evidence of angina occurred and if no new no ECG ST-T alteration of ischemia developed Therefore amiloride withwithout aspirin Statins and medication for hypertension or diabetes will be the established treatment until the end of trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None