AU9402498A - Use of quinapril for treating myocardial ischemia and angina - Google Patents

Description

WO 99/22736 PCT/US98/19737 -1 USE OF QUINAPRIL FOR TREATING MYOCARDIAL ISCHEMIA AND ANGINA FIELD OF THE INVENTION This invention relates to a method for preventing and treating myocardial 5 ischemia, and in particular angina, by administering to a mammal at risk or in need of treatment an effective amount of quinapril or quinaprilat. BACKGROUND OF THE INVENTION Numerous agents known as inhibitors of angiotensin converting enzyme (ACE) are routinely used to treat conditions in mammals associated with elevated 10 blood pressure. Several of these agents, including quinapril, are also indicated for treatment of congestive heart failure. These are severe cardiovascular disorders, often resulting from advanced coronary artery disease, and family history. Numerous people suffer from less severe cardiovascular disorders such as daily life ischemia and angina, particularly angina pectoris, which is a paroxysmal 15 thoracic pain, with a feeling of suffocation and impeding death, due, most often, to insufficient oxygenated blood supply to the myocardium and precipitated by effort or excitement. Angina pectoris is also known as Elsner's asthma, Heberden's asthma, Rougnon-Heberden disease, and stenocardia. Daily life ischemia is a condition of deficiency of blood in a part of the myocardium, due to 20 functional constriction or actual obstruction of a blood vessel. Such conditions are also referred to as silent ischemia or ischemia of daily life, and frequently occur spontaneously with ordinary activities and emotions. Silent ischemia occurs with a circadian rhythm so that the majority of episodes are seen in the first six waking hours of the day when neurohormonal activation increases. Silent, daily life 25 ischemia is not totally due to increased myocardial oxygen demand, since it occurs at a heart rate and systolic blood pressure significantly lower than ischemia induced by exercise. Silent, daily life ischemia, is associated with adverse outcomes such as chronic stable angina, unstable angina, and recurrence of WO 99/22736 PCT/US98/19737 -2 myocardial infarction, worsening heart failure, and sudden death. Studies have established that about one-fourth of the patients diagnosed with daily life ischemia (e.g. by ambulatory ECG), encounter one or more adverse outcomes at 1 year following the diagnosis (e.g. hospitalization because of ischemia-related reasons, 5 myocardial infarction, and death). We have now discovered that quinapril and quinaprilat are effective in preventing and treating myocardial ischemia, and the more severe angina pectoris. These agents are unexpectedly superior to other ACE inhibitors in their ability to improve myocardial blood flow to ischemic regions in coronary arteries, and 10 concomitantly decrease coronary resistance in patients with coronary artery disease. The compounds also are surprisingly more effective than other ACE inhibitors in reducing the frequency and severity of myocardial ischemia by improving endothelial-mediated vasomotion and endothelium-dependent flow mediated vasodilation. 15 SUMMARY OF THE INVENTION This invention provides a method for preventing myocardial ischemia and angina in mammals by administering to a mammal at risk or in need of treatment an effective amount of quinapril or quinaprilat. The invention also provides a method for improving endothelial function comprising administering quinapril or 20 quinaprilat. A preferred embodiment employs quinapril, especially as a pharmaceutically acceptable salt, most preferably the hydrochloride salt. Quinapril hydrochloride is 2-[2-(1-Ethoxycarbonyl-3-phenyl-propylamino)-propionyl] 1, 2

,

3

,

4 -tetrahydroisoquinoline-3-carboxylic acid monohydrochloride. It is 25 commercially available and can be utilized as a hydrate, if desired. Another preferred embodiment employs quinaprilat, which is the diacid form of quinapril. Quinaprilat is 2-[2-(1-Carboxy-3-phenyl-propylamino) propionyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. Another embodiment of this invention is a method for improving coronary 30 endothelial function by administering quinapril or quinaprilat.

WO 99/22736 PCT/US98/19737 -3 DESCRIPTION OF FIGURES Figure 1 shows the reduction in ischemic events and episodes of silent ischemia on Holter recording at 1 year following coronary artery bypass grafting (CABG) in patients treated with quinapril. 5 Figure 2 shows the effectiveness of quinapril, enalapril, losartan, and amlodipine in improving human endothelial function in patients with documented coronary disease. Figure 3a shows the normal (control) blood flow to non-ischemic and to ischemic regions of the myocardium during rest and during stress conditions. 10 Figure 3b shows the blood flow to non-ischemic and to ischemic regions of the myocardium following an IV dosing of quinaprilat. Figure 4a shows the normal (control) coronary resistance of non-ischemic regions and ischemic regions during rest and during stress conditions. Figure 4b shows the total coronary resistance of non-ischemic regions and 15 ischemic regions in patients treated with IV infusions of quinaprilat. DETAILED DESCRIPTION OF THE INVENTION In practicing the methods of this invention, quinapril and quinaprilat will be formulated in their current or substantially equivalent commercially available preparations, and utilized at their normal and customary dosage levels for treating 20 hypertension and congestive heart failure. For example, quinapril hydrochloride is formulated with common excipients such as cardelilla wax, crospovidone, gelatin, lactose, magnesium carbonate, magnesium stearate, synthetic red iron oxide, and titanium dioxide. The preparation is available as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of quinapril hydrochloride for oral administration. Quinaprilat 25 can be similarly formulated and supplied in tablets, capsules, skin patches, suppositories, solutions, or other forms for convenient parentereal or oral administration. The "effective amount" required to practice the method of this invention is thus that amount of quinapril, a salt thereof, or quinaprilat which WO 99/22736 PCT/US98/19737 -4 causes improvement in endothelial function and results in prevention or control of ischemia and angia. The ability of quinapril and quinaprilat to improve coronary endothelial function and to prevent and treat ischemia and angina has been established in 5 several multi-patient clinical trials. The following detailed examples describe various clinical trials. EXAMPLE 1 This trial was specifically designed to evaluate the ability of quinapril to reduce ischemic events and to prevent or reduce symptoms of angina. This study 0 was a sixteen (16) week, randomized, double-blind, placebo-controlled, parallel group multicenter study. The study utilized 450 patients with diagnosed coronary artery disease. Eligible patients have ischemia as established by exercise treadmill testing, with at least one or more ischemic episodes of at least one millimeter or more of ST depression during 48-hour ambulatory ECG monitoring. Patients with 5 revascularization within 6 months, uncontrolled hypertension, heart failure, and insulin-dependent diabetes were excluded from the trial. The primary efficacy parameter is exercise time to 1 mm ST depression (a measure of ischemia) on treadmill exercise testing after 8 weeks of oral treatment with quinapril. Secondary efficacy parameters include frequency and duration of ischemic 0 episodes on ambulatory ECG monitoring at 4, 8, and 16 weeks, and exercise duration on exercise treadmill testing at 8 and 16 weeks. The study has 80% power to detect a 50% change in ischemic episodes between treatment with quinapril versus placebo. Present baseline characteristics reveal a mean age of 67, 78% males and 22% females, a median of four ischemic episodes on ambulatory 5 ECG monitoring, each having an average of 12.7 minutes in duration. The study group also has a mean exercise time of 216 seconds until angina occurs. Patients who are not receiving aspirin prior to the study are required to take an initial dose of 162 mg (two 81-mg tablets) at the first screening visit, and are maintained indefinitely at a dose of at least 81 mg per day throughout the study. All patients 0 who are receiving aspirin at a dose of at least 81 mg per day or greater at the initiation of the study remain on that dose throughout the study.

WO 99/22736 PCT/US98/19737 -5 Patients receive a drug container with a 34-day supply of double-blinded quinapril tablets or placebo. During the double-blind phase, patients will be dispensed a new supply of medication at each visit after returning the containers dispensed at the previous visit. Patients are instructed to take two tablets at the 5 same time every day, one from Bottle A and one from Bottle B. One half of the enrolled patients will take quinapril at 40 mg per day, starting at initiation of the study, and continuing at that dosage throughout the entire 16-week trial. The other half of the enrolled patients will consume placebo during the first 8 weeks of the trial, and then will receive 80 mg per day of quinapril during the remaining 10 8-week period. EXAMPLE 2 Another clinical trial was conducted to measure the effects of quinapril on vascular angiotensin converting enzyme and determinants of ischemia. This study was designed to evaluate the efficacy of 1 year treatment with quinapril on 15 myocardial ischemia in patients who underwent elective arterial coronary artery bypass surgery. In this study, 149 patients who were scheduled for coronary artery bypass grafting (CABG) were randomized into placebo and treatment groups approximately 27 days before surgery. Prior to surgery, all patients received an oral test dose of 5 mg of quinapril to assess tolerability. Blood pressure was 20 measured 2 hours after ingestion, and routine blood chemistry (sodium, potassium and creatinin) were determined immediately before CABG. Patients were given placebo or quinapril hydrochloride (two 20-mg tablets each day following surgery for 1 year). Baseline characteristics were comparable between the placebo treated group and the quinapril treated group. The patients 25 were dosed daily for 1 year following CABG, at which time an exercise test was performed on each patient. A 48-hour Holter was also performed after the 1-year treatment period. All clinical ischemic events, including re-onset of angina pectoris, myocardial infarction, ischemic stroke, or transient ischemic attack were recorded. 30 Overall, total exercise duration increased by 77 ± 7 seconds for all trial patients. Ischemic ST segment changes were present in all study patients at randomization (prior to CABG), and in 33% of all patients 1 year after surgery. A WO 99/22736 PCT/US98/19737 -6 significant reduction in clinical ischemic events was demonstrated for the quinapril treated group (4% of patients receiving quinapril hydrochloride had ischemic events versus 18% of placebo treated patients). These data are shown in Figure 1. On 48-hour Holter monitoring, 20% of the placebo patients had one or 5 more ischemic episodes, versus 13% of the patients receiving quinapril hydrochloride. The results of this study demonstrates that a clinically relevant risk reduction (RR) of ischemic events is achieved by administering quinapril hydrochloride (see Figure 1). EXAMPLE 3 10 In another clinical study, quinapril hydrochloride was compared to several other cardiovascular agents to determine its relative ability to improve endothelial function and blood flow-mediated dilation in the brachial artery of the forearm. Improved endothelial function leads to a reduction in ischemia and angina. High resolution ultrasound was used to compare the chronic effects of four anti 15 hypertensive agents (quinapril hydrochloride, enalapril, losartan, and amlodipine) on brachial artery flow-mediated vasodilation (FMD) in patients diagnosed with coronary artery disease. Patients were enrolled in a partial-block, cross-over design trial, and randomized in one of four different open label drug treatment groups. Brachial artery flow-mediated vasodilation was evaluated before drug 20 treatment, and again after 8 weeks of treatment with each study drug. The high resolution ultrasound analysis established that patients having coronary artery disease have significantly impaired FMD (6.2 + 0.6%, n = 80) compared to normal patients (10.9 ± 0.8%, n = 40, p <0.05). Quinapril hydrochloride was the only anti-hypertensive agent in this study which caused a 25 clinically significant improvement in flow-mediated dilation. The results are shown in Figure 2. Absolute changes in FMD are presented in Table 1 below: TABLE 1. Reduction in Endothelial Function Drug Daily N Absolute Change in p-Value Dose (mg) FMD (mean ± SE) Quinapril Hydrochloride 20 56 1.8 ± 1.0% <0.02 Enalapril 10 55 -0.2 ± 0.8% 0.84 Losartan 50 38 0.8 ± 1.1% 0.57 Amlodipine 5 45 0.3 ± 0.9% 0.97 WO 99/22736 PCT/US98/19737 -7 The foregoing data established that quinapril is surprisingly superior to other ACE inhibitors in its ability to improve endothelial function. EXAMPLE 4 This study was designed to measure the regional changes in myocardial 5 blood flow caused by quinaprilat. Twelve normotensive patients diagnosed with single vessel coronary artery disease and normal left ventricular function were enrolled. The patients were analyzed by [150] water positron emission tomography at rest, and during maximal stress caused by administering dobutamine hydrochloride intravenously, a commonly used inotropic agent which 10 is known to place stress on the myocardium. The imaging sequence was performed prior to administering quinaprilat, and then repeated following a 10 mg IV dose of quinaprilat. Of the 12 normotensive patients, 9 were men with a mean age of 59 years. Each patient had either a positive exercise stress ECG (ST-segment depression 15 >0.2 mV, n = 8) or a positive thallium scan (n = 4), a proximal high grade stenosis in a coronary artery (>70% diameter reduction) and normal left ventricular function. Ten patients had a stenosis of the left anterior descending artery and two of the left circumflex artery. Positron emission tomography (PET) was performed using a whole body 20 scanner (Siemans CTI ECAT EXACT 921) that had an axial field of view of 16.2 cm. Each patient was given 50 g of oral glucose 30 minutes prior to starting the PET scan to enhance myocardial glucose uptake. Each patient was then started on a rest [150O] water scan by injecting intravenously 15 to 20 mCi of [150O] water as a slow bolus over 30 seconds. Fifteen cross-sectional images were obtained for 25 180 seconds (6 for 5 seconds, 10 for 15 seconds). After completion of the first [150O] water PET scan, myocardial stress was initiated by IV infusion of dobutamine (maximal dosage 40 gg/kg/min). A second [150O] water scan was started during the maximal dose of dobutamine 2 minutes before the end of the stress test. If systolic blood pressure after completion of the second [150O] water 30 scan was higher than 100 mmHg, a dose of 10 mg of quinaprilat was administered IV over 5 minutes. The patients remained on the PET scanner for another 30 WO 99/22736 PCT/US98/19737 -8 minutes, without changing in position. The rest/stress protocol was then repeated. Following completion of the second stress protocol, the patient was given 10 mCi of [18F] fluoro-deoxy-glucose, and another PET scan was carried out over 30 minutes (emission scan of six images for 5 minutes each). 5 All sets of PET images (rest/stress with and without quinaprilat) were number coded and randomly analyzed (image selection and drawing and placing of the regions of interest) by two observers. Images were corrected for attenuation, random events, deadtime losses, and scattered radiation. The deadtime losses were less than 15% for all studies. 0 Figure 3a shows the myocardial blood flow (mL/min/g) at rest and under stress for both normal regions of the myocardium and for the regions determined to be ischemic. Of the 60 regions assigned to the test patients, 22 regions in the area supplied by the stenosed coronary artery were found to be ischemic, the remaining 38 regions served as control regions. Figure 3a shows that the blood 5 flow in the normal control (non-ischemic) regions increased (before quinaprilat treatment) during stress (precipitated by dobutamine infusion), going from 0.90 mL/min/g to 2.3 mL/min/g, whereas in the ischemic regions, blood flow was the same during rest and during stress (1.2 mL/min/g). Figure 3b shows the effect of quinaprilat on myocardial blood flow. After quinaprilat IV dosing, myocardial 0 blood flow at rest remained similar in the control and ischemic regions (1.1 mL/min/g). During dobutamine stress, the increase in myocardial blood flow in control regions was similar before and after quinaprilat. However, blood flood in the ischemic regions improved significantly (1.2 to 1.9 mL/min/g). Accordingly, coronary reserve in ischemic regions increased significantly after 15 quinaprilat treatment, but was significantly lower than the coronary reserve in control regions after quinaprilat dosing. Total coronary resistance (mmHg-min-g/mL) before and after quinaprilat, for both control- regions and ischemic regions, is shown in Figures 4a and 4b. The data establish that total coronary resistance decreased significantly in control 0 regions during dobutamine stress, both before and after treatment with quinaprilat. In contrast, total coronary resistance in ischemic regions remained initially WO 99/22736 PCT/US98/19737 -9 unchanged during dobutamine stress, but decreased significantly after quinaprilat infusion during dobutamine stress. The data from the foregoing clinical trials establish that quinapril and quinaprilat are surprisingly effective in preventing and treating ischemia and 5 angina, and for improving endothelial function in humans. The compounds can be administered in therapeutic amounts to patients having a family history of coronary artery disease, or otherwise are at risk for developing such disease, thus leading to myocardial ischemia and angina pectoris. The compounds can additionally be administered to patients suffering from myocardial ischemia or 0 angina and in need of treatment. The precise treatment, for example dosing, frequency of dosing, exercise, and combination with other drugs, will be dictated by an attending physician or other medial practitioner.

Claims (6)

1. A method for preventing or treating myocardial ischemia comprising administering to a mammal at risk or in need of treatment an effective 5 amount of quinapril, a pharmaceutically acceptable salt thereof or quinaprilat.

2. The method of Claim 1 employing quinapril hydrochloride.

3. The method of Claim 1 employing quinaprilat.

4. The method of Claim 1 wherein the myocardial ischemia is angina. 0

5. A method for improving endothelial function in a mammal comprising administering an effective amount of quinapril, a pharmaceuticaly acceptable salt thereof, or quinaprilat.

6. The method of Claim 5 comprising administering quinapril hydrochloride.