WO1999022736A1 - Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine - Google Patents

Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine Download PDF

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Publication number
WO1999022736A1
WO1999022736A1 PCT/US1998/019737 US9819737W WO9922736A1 WO 1999022736 A1 WO1999022736 A1 WO 1999022736A1 US 9819737 W US9819737 W US 9819737W WO 9922736 A1 WO9922736 A1 WO 9922736A1
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WO
WIPO (PCT)
Prior art keywords
quinapril
patients
quinaprilat
angina
ischemic
Prior art date
Application number
PCT/US1998/019737
Other languages
English (en)
Inventor
Donald Michael Black
Milton Lethan Presler
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to BR9814114-7A priority Critical patent/BR9814114A/pt
Priority to KR1020007004856A priority patent/KR20010031789A/ko
Priority to JP2000518669A priority patent/JP2001521898A/ja
Priority to CA002300198A priority patent/CA2300198A1/fr
Priority to AU94024/98A priority patent/AU9402498A/en
Priority to EP98947190A priority patent/EP1028728A1/fr
Publication of WO1999022736A1 publication Critical patent/WO1999022736A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to a method for preventing and treating myocardial ischemia, and in particular angina, by administering to a mammal at risk or in need of treatment an effective amount of quinapril or quinaprilat.
  • ACE angiotensin converting enzyme
  • Angina pectoris is also known as Eisner'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 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 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 myocardial infarction, worsening heart failure, and sudden death.
  • adverse outcomes such as chronic stable angina, unstable angina, and recurrence of 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, myocardial infarction, and death).
  • 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 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.
  • 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 quinaprilat.
  • a preferred embodiment employs quinapril, especially as a pharmaceutically acceptable salt, most preferably the hydrochloride salt.
  • Quinapril hydrochloride is 2-[2-(l -Ethoxycarbonyl-3-phenyl-propylamino)-propionyl]- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid monohydrochloride. It is commercially available and can be utilized as a hydrate, if desired.
  • Quinaprilat is the diacid form of quinapril.
  • Quinaprilat is 2-[2-(l-Carboxy-3-phenyl-propylamino)- propionyl]-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
  • Another embodiment of this invention is a method for improving coronary endothelial function by administering quinapril or quinaprilat.
  • 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.
  • Figure 2 shows the effectiveness of quinapril, enalapril, losartan, and amlodipine in improving human endothelial function in patients with documented coronary disease.
  • Figure 3 a shows the normal (control) blood flow to non-ischemic and to ischemic regions of the myocardium during rest and during stress conditions.
  • 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 ischemic regions in patients treated with IV infusions of quinaprilat.
  • 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 hypertension and congestive heart failure.
  • 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 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 causes improvement in endothelial function and results in prevention or control of ischemia and angia.
  • 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 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 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 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 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 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. 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 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 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 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 measured 2 hours after ingestion, and routine blood chemistry (sodium, potassium and creatinin) were determined immediately before CABG.
  • CABG coronary artery bypass grafting
  • 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 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. 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.
  • EXAMPLE 4 This study was designed to measure the regional changes in myocardial 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 [ 15 O] water positron emission tomography at rest, and during maximal stress caused by administering dobutamine hydrochloride intravenously, a commonly used inotropic agent which 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.
  • PET Positron emission tomography
  • 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 [ 15 O] water scan by injecting intravenously 15 to 20 mCi of [ 15 O] water as a slow bolus over 30 seconds. Fifteen cross-sectional images were obtained for 180 seconds (6 for 5 seconds, 10 for 15 seconds). After completion of the first
  • Figure 3 a 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 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 blood flow at rest remained similar in the control and ischemic regions
  • 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 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.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Prévention et traitement de l'ischémie myocardique et de l'angine de poitrine à l'aide de quinapril et de quinaprilat.
PCT/US1998/019737 1997-11-05 1998-09-22 Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine WO1999022736A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9814114-7A BR9814114A (pt) 1997-11-05 1998-09-22 Uso de quinapril para o tratamento de isquemia miocárdica e angina
KR1020007004856A KR20010031789A (ko) 1997-11-05 1998-09-22 퀴나프릴의 심근 허혈증 및 앙기나 치료용 용도
JP2000518669A JP2001521898A (ja) 1997-11-05 1998-09-22 心筋虚血およびアンギナの処置のためのキナプリルの使用
CA002300198A CA2300198A1 (fr) 1997-11-05 1998-09-22 Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine
AU94024/98A AU9402498A (en) 1997-11-05 1998-09-22 Use of quinapril for treating myocardial ischemia and angina
EP98947190A EP1028728A1 (fr) 1997-11-05 1998-09-22 Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6428697P 1997-11-05 1997-11-05
US60/064,286 1997-11-05

Publications (1)

Publication Number Publication Date
WO1999022736A1 true WO1999022736A1 (fr) 1999-05-14

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PCT/US1998/019737 WO1999022736A1 (fr) 1997-11-05 1998-09-22 Utilisation de quinapril dans le traitement de l'ischemie myocardique et de l'angine de poitrine

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EP (1) EP1028728A1 (fr)
JP (1) JP2001521898A (fr)
KR (1) KR20010031789A (fr)
AU (1) AU9402498A (fr)
BR (1) BR9814114A (fr)
CA (1) CA2300198A1 (fr)
WO (1) WO1999022736A1 (fr)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
B.R. WINKELMANN ET AL.: "Antianginal effects of quinapril in patients with coronary artery disease.", EUR. HEART J., vol. 12, 1991, pages 355, XP002091748 *
M. TEXER ET AL.: "The QUinapril Ischemic Event Trial (QUIET) design and methods: evaluation of chronic ACE inhibitor therapy after coronary artery intervention.", CARDIOVASC. DRUGS THERAP., vol. 7, no. 2, 1993, pages 273 - 282, XP002091750 *
W.D. BUSSMAN ET AL.: "Angiotensin-converting-enzym-Hemmer bei Angina pectoris", DTSCH. MED. WOCHENSCHR., vol. 113, no. 14, 1988, pages 548 - 550, XP002091749 *

Also Published As

Publication number Publication date
JP2001521898A (ja) 2001-11-13
CA2300198A1 (fr) 1999-05-14
KR20010031789A (ko) 2001-04-16
BR9814114A (pt) 2000-10-03
AU9402498A (en) 1999-05-24
EP1028728A1 (fr) 2000-08-23

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