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WO1999009967A2 - Therapie hypocholesterolemiante - Google Patents

Therapie hypocholesterolemiante Download PDF

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Publication number
WO1999009967A2
WO1999009967A2 PCT/US1998/017459 US9817459W WO9909967A2 WO 1999009967 A2 WO1999009967 A2 WO 1999009967A2 US 9817459 W US9817459 W US 9817459W WO 9909967 A2 WO9909967 A2 WO 9909967A2
Authority
WO
WIPO (PCT)
Prior art keywords
subject
hmg
coa reductase
reductase inhibitor
density lipoprotein
Prior art date
Application number
PCT/US1998/017459
Other languages
English (en)
Other versions
WO1999009967B1 (fr
WO1999009967A3 (fr
Inventor
Edwin J. Whitney
Geraldine Mantell
Original Assignee
Merck & Co., Inc.
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
Priority claimed from GBGB9814415.7A external-priority patent/GB9814415D0/en
Priority claimed from GBGB9815851.2A external-priority patent/GB9815851D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002300165A priority Critical patent/CA2300165A1/fr
Priority to EP98943329A priority patent/EP1007019A2/fr
Priority to AU91153/98A priority patent/AU9115398A/en
Publication of WO1999009967A2 publication Critical patent/WO1999009967A2/fr
Publication of WO1999009967A3 publication Critical patent/WO1999009967A3/fr
Publication of WO1999009967B1 publication Critical patent/WO1999009967B1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring

Definitions

  • the instant invention involves a method of using a cholesterol reducing agent such as a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) alone or in combination with other lipid altering agents for preventing or reducing the risk of first occurrence of a cardiovascular event.
  • a cholesterol reducing agent such as a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) alone or in combination with other lipid altering agents for preventing or reducing the risk of first occurrence of a cardiovascular event.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • lovastatin, simvastatin, and pravastatin which are members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries.
  • Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events in patients with hypercholesterolemia and/or CHD, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided evidence for a reduction in cerebrovascular events. Additional studies have shown that HMG Co A RI's may have an effect on platelet aggregation.
  • One object of the instant invention is to provide a novel method for preventing or reducing the risk of a first occurrence of a cardiovascular event in a subject having an average to mildly elevated level of LDL cholesterol, and below average high-density lipoprotein (HDL) cholesterol, with no clinical evidence of coronary heart disease, comprising administering a prophylactically effective amount of a lipid altering agent such as an HMG-CoA reductase inhibitor either alone or in combination with another lipid altering agent such as a fibrate, or niacin to the subject.
  • a lipid altering agent such as an HMG-CoA reductase inhibitor
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR®; see US Patent No. 4,231,938), simvastatin (ZOCOR®; see US Patent No. 4,444,784), pravastatin (PRAVACHOL®; see US Patent No. 4,346,227), fluvastatin (LESCOL®; see US Patent No. 5,354,772), atorvastatin (LIPITOR®; see US Patent No. 5,273,995) and cerivastatin (also known as rivastatin; see US Patent No. 5,177,080), and the pharmaceutically acceptable salt, ester and lactone forms thereof.
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85- 89 (5 February 1996).
  • the HMG-CoA RI is selected from lovastatin, cerivastatin, atorvastatin, pravastatin and simvastatin, a sub-class comprises simvastatin and lovastatin.
  • fibrates that may be used in combination with the HMG-CoA RI include, but are not limited to benzofibrate, ciprofibrate, fenofibrate, gemfibrazol and clofibrate.
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters and lactone forms is included within the scope of this invention.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • salts shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base.
  • suitable organic or inorganic base examples include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesy
  • Prophylactically effective amounts of the HMG-CoA reductase inhibitors are suitable for use in the compositions and methods of the present invention.
  • the term "prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage regimen utilizing an HMG-CoA RI is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt or ester thereof employed.
  • the prophylactically effective amount to be used in the methods of this invention is that amount of drug sufficient to lower the human subject's LDL cholesterol to a target level of 130 mg/dl or less; in a sub-embodiment to a target level of 115 mg/dl or less; and in a further sub-embodiment to a target level of 110 mg/dl or less.
  • lipid altering agent such as an HMG-CoA RI which, when taken on a daily basis, will allow the patient to reach this goal.
  • patient or “subject” includes mammals, especially humans, who take a lipid altering agent for any of the uses described herein.
  • Administration of the lipid altering agent to the subject includes both self-administration and administration to the subject by another person.
  • HMG-CoA reductase inhibitor Dosage information for HMG-CoA RI's is well known in the art, since several are marketed in the U.S.
  • the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti- hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR).
  • PDR Physicians' Desk Reference
  • the oral dosage amount of HMG-CoA RI is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day.
  • dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above.
  • An HMG-CoA RI which has sufficiently greater potency may be given in sub-milligram daily dosages.
  • the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 mg, 40 mg, and 80 mg; for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg.
  • the daily dosage amount for cerivastatin may be in the range of from 0.1 mg to 0.8 mg, and more particularly from 0.2 mg to 0.8 mg, including dosage amounts of 0.2 mg, 0.3 mg, 0.4 mg and 0.8 mg.
  • Oral administration may be in single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA RI is preferred.
  • HMG-CoA reductase inhibitors are well-known to those skilled in the art, as evidenced by the information provided in the 1996 PDR. While the HMG-CoA reductase inhibitor can be administered orally or parenterally, oral dosing is preferred.
  • the active agents employed in the instant therapy can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Oral formulations are preferred.
  • the instant invention includes the use of oral rapid-release as well as time-controlled release pharmaceutical formulations, particularly as described in U.S. Patent No. 5,366,738.
  • the active drug can be administered in admixture with pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms.
  • suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • the active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide- phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • cardiovascular event includes but is not limited to fatal and non-fatal acute major coronary events, coronary revascularization procedures, peripheral vascular disease, stable angina, and cerebrovascular insufficiency such as stroke.
  • acute major coronary event is intended to include fatal myocardial infarction; witnessed and unwitnessed sudden cardiac death and sudden death occurring from 1 hour up to 24 hours after collapse; non-fatal myocardial infarction including definite acute Q-wave myocardial infarction, non-Q-wave myocardial infarction, and silent subclinical (remote) myocardial infarction; and unstable angina pectoris.
  • myocardial infarction is intended to include both Q-wave and non-Q-wave myocardial infarction and silent subclinical (remote) myocardial infarction.
  • Subjects to be treated with the instant methods are those having an average to mildly elevated serum total cholesterol level, which is intended herein to be a level less than or equal to about 260 mg/dl.
  • the patients to be treated may have a serum total cholesterol level of less than or equal to 240 mg/dl, and more particularly under 200 mg/dl.
  • the subjects to be treated may have a serum total cholesterol level from 180 mg/dl to 264 mg/dl.
  • the subjects to be treated have a below average high-density lipoprotein cholesterol level, i.e., less than or equal to 50 mg/dl, and an average to mildly elevated low-density lipoprotein cholesterol level, i.e., less than or equal to 190 mg/dl, prior to treatment.
  • the low- density lipoprotein cholesterol level is 130 mg/dl to 190 mg/dl prior to treatment.
  • the LDL-cholesterol is ⁇ 130 mg/dl if the ratio of total cholesterol to HDL-cholesterol is > 6.
  • the subjects to be treated also have no clinically evident coronary heart disease.
  • a prophylactically effective amount of an HMG-CoA RI or a combination with another lipid altering agent can be used for the preparation of a medicament useful for preventing or reducing the risk of a first occurrence of a cardiovascular event in a subject having an average to mildly elevated level of serum total cholesterol, an average to mildly elevated level of low- density lipoprotein cholesterol, and a below average level of high-density lipoprotein cholesterol.
  • a clinical trial referred to herein as "AFCAPS/TexCAPS” or "AFCAPS” employing lovastatin to exemplify the methods of the present invention.
  • AFCAPS/TexCAPS was a primary prevention endpoint event trial which: (1) included unstable angina as a primary endpoint, reflecting the trend to treat coronary heart disease aggressively before a myocardial infarction has occurred; 2) involved aggressive pharmacologic intervention, with titration, to target an LDL-cholesterol goal lower than current National Cholesterol Education Panel guidelines for primary prevention; and 3) included a cohort comprised of men and women with a broad age range encompassing the elderly and included persons with a lipid profile consisting of average total and LDL-cholesterol, below average HDL-cholesterol levels; total cholesterol/HDL-cholesterol ratio greater than or equal to 4.5, with a baseline mean ratio of 6.1 for the cohort; and LDL/HDL-cholesterol ratio greater than or equal to 4. Entrance inclusion criteria were LDL-cholesterol 130-190 mg/dl (or ⁇ 130 if the ratio of total cholesterol/HDL is > 6) and HDL- cholesterol ⁇ 45 mg/dl for men and ⁇ 47 mg/
  • AFCAPS/TexCAPS was a double-blind, randomized, placebo controlled trial designed and powered to investigate whether chronic lipid-lowering, with lovastatin will decrease the rate of first acute major coronary events (e.g. sudden cardiac death, fatal and non- fatal myocardial infarction and unstable angina) compared to intervention with diet alone during at least 4.5 years of follow-up in a cohort without clinical evidence of atherosclerotic cardiovascular disease and with average to mildly elevated total cholesterol, average to midly elevated LDL-cholesterol, and below average HDL-cholesterol.
  • first acute major coronary events e.g. sudden cardiac death, fatal and non- fatal myocardial infarction and unstable angina
  • Atherosclerotic cardiovascular disease Excluded for clinical evidence of atherosclerotic cardiovascular disease were men and women who had: prior history of myocardial infarction; angina; claudication; cerebrovascular accident; or transient ischemic attack. Also excluded were those aged > 73 years or ⁇ 45 years (men) or ⁇ 55 years (women) or those with secondary hyperlipoproteinemia, nephrotic syndrome, uncontrolled or insulin- dependent diabetes mellitus or uncontrolled hypertension. At their discretion, investigators also could have excluded those who would have difficulty completing a study of at least 5 years duration (e.g. due to compliance problems or reduced life expectancy).
  • Baseline risk factors in the tested population were as follows: Family history of premature coronary artery disease: 16%; Active cigarette smoker: 12%; Hypertension: 22%; Diabetes: 2%. HDL ⁇ 35 mg/dL: 35% Participants were randomized to either placebo or lovastatin
  • Baseline measurements on the day of randomization included lipid analysis (including Apo Al and Apo B), hematology, blood chemistry and urinalysis.
  • participant in the lovastatin treatment group could be titrated to lovastatin 40 mg once a day based upon LDL-cholesterol values at 6 and 12 weeks after randomization.
  • Participants in the lovastatin treatment group with LDL-cholesterol > 110 mg/dl at both visits were titrated at week 18 to 40 mg once a day of lovastatin by taking two 20 mg tablets once a day.
  • an equal number of randomly selected participants in the placebo treatment group were also titrated to two tablets per day.
  • an equal number from the titrated placebo group also had their doses reduced.
  • the primary endpoint events included sudden cardiac death, fatal and non-fatal myocardial infarction and unstable angina. They are defined as follows: I . Fatal Myocardial Infarction or Sudden Cardiac Death
  • Non-Q-Wave Myocardial Infarction includes myocardial infarctions reperfused by either mechanical or pharmacologic means providing there is supporting ECGs and enzyme data • Silent Subclinical (Remote) Myocardial Infarction - definitive
  • ECG ECG
  • ECG or, if ECG is equivocal, focal wall motion abnormality consistent with myocardial infarction on rest echo or stress thallium (fixed defect) and on catheterization, a >50% stenosis in a major corresponding epicardial vessel.
  • Participants who have had a cardiac catheterization as the first diagnostic test for presumed silent (or remote) myocardial infarction are considered to have met criteria for an endpoint event if the catheterization findings indicate focal wall abnormalities consistent with myocardial infarction and 50% stenosis in a corresponding artery
  • 'angina' was adjudicated as a secondary endpoint event if, prior to the hospitalization, the participant was asymptomatic for > 2 weeks or has been stable for > 1 month (defined as 28 days) even if the criteria for 'unstable angina', noted above, were met.
  • the risk of an acute major coronary event using lovastatin was reduced by at least about 20% and more particularly about 21% to 50%, and illustratively about 30% to 40%.
  • the risk reduction of an acute major coronary event with simvastatin, pravastatin, fluvastatin, cerivastatin, or atorvastatin is also expected to be at least about 20%, and more particularly about 21% to 50%, and illustratively about 30% to 40%.
  • the risk of a fatal and non-fatal cardiovascular event using lovastatin was reduced by at least about 9% and more particularly about 9% to 38%, and illustratively about 20% to 30%.
  • the risk reduction of a fatal or non-fatal cardiovascular event with simvastatin, pravastatin, fluvastatin, cerivastatin or atorvastatin is also expected to be at least about 9%, and more particularly about 9% to 38%, and illustratively about 20% to 30%.
  • the risk of unstable angina using lovastatin was reduced by at least about 5% and more particularly about 5% to 52%, and illustratively about 25% to 40%.
  • the risk reduction of unstable angina with simvastatin, pravastatin, fluvastatin, cerivastatin, or atorvastatin is also expected to be at least about 5%, and more particularly about 5% to 52%, and illustratively about 25% to 40%.
  • the risk of revascularization using lovastatin was reduced by at least about 15% and more particularly about 15% to 48%, and illustratively about 30% to 40%.
  • the risk reduction of revascularization with simvastatin, pravastatin, fluvastatin, cerivastatin, or atorvastatin is also expected to be at least about 15%, and more particularly about 15% to 48%, and illustratively about 30% to 40%.
  • the risk of a fatal or non-fatal myocardial infarction using lovastatin was reduced by at least about 17% and more particularly about 17-57%, and illustratively, about 30-50%.
  • the risk reduction of a fatal or non-fatal myocardial infarction using simvastatin, pravastatin, fluvastatin, cerivastatin or atorvastatin is also expected to be at least about 17%, and more particularly about 17- 57%, and illustratively, about 30-50%.
  • LDL-C LDL-cholesterol
  • HDL-C HDL-cholesterol
  • lovastatin was independent of baseline LDL-C and HDL-C, thus demonstrating that benefit is conferred even in those subjects in the lowest LDL-C tertile. Similar results are also expected to be achieved with simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes de prévention ou de réduction du risque d'un premier accident cardio-vasculaire, à l'aide d'un inhibiteur de HMG-CoA-réductase seul ou en combinaison avec un autre agent modifiant les lipides. Les sujets à traiter sont ceux qui présentent un taux de cholestérol total sérique moyen, un taux sérique de cholestérol dans les lipoprotéines de basse densité moyen à légèrement élevé et un taux sérique de cholestérol dans les lipoprotéines de haute densité en dessous de la moyenne, sans antécédents de maladies coronariennes cliniquement déclarées.
PCT/US1998/017459 1997-08-26 1998-08-21 Therapie hypocholesterolemiante WO1999009967A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002300165A CA2300165A1 (fr) 1997-08-26 1998-08-21 Therapie hypocholesterolemiante
EP98943329A EP1007019A2 (fr) 1997-08-26 1998-08-21 Therapie hypocholesterolemiante
AU91153/98A AU9115398A (en) 1997-08-26 1998-08-21 Cholesterol-lowering therapy

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US5696697P 1997-08-26 1997-08-26
US60/056,966 1997-08-26
US7685998P 1998-03-05 1998-03-05
US60/076,859 1998-03-05
US8536098P 1998-05-13 1998-05-13
US60/085,360 1998-05-13
GB9814415.7 1998-07-03
GBGB9814415.7A GB9814415D0 (en) 1998-07-03 1998-07-03 Cholesterol-lowering therapy
GB9815851.2 1998-07-21
GBGB9815851.2A GB9815851D0 (en) 1998-07-21 1998-07-21 Cholesterol-lowering therapy

Publications (3)

Publication Number Publication Date
WO1999009967A2 true WO1999009967A2 (fr) 1999-03-04
WO1999009967A3 WO1999009967A3 (fr) 1999-05-20
WO1999009967B1 WO1999009967B1 (fr) 1999-07-08

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PCT/US1998/017459 WO1999009967A2 (fr) 1997-08-26 1998-08-21 Therapie hypocholesterolemiante

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EP (1) EP1007019A2 (fr)
AU (1) AU9115398A (fr)
CA (1) CA2300165A1 (fr)
WO (1) WO1999009967A2 (fr)

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ES2246894T3 (es) 1999-08-30 2006-03-01 Sanofi-Aventis Deutschland Gmbh Ramipril para la prevencion de sucesos cardiovasculares.
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
IL156422A0 (en) 2001-01-26 2004-01-04 Schering Corp The use of substituted azetidinone compounds for the treatment of sitosterolemia
CA2563051A1 (fr) 2001-01-26 2002-08-01 Schering Corporation Combinaisons d'au moins un activateur de recepteurs actives de la proliferation des peroxysomes et d'au moins un inhibiteur de l'absorption des sterols, et traitements de troublesvasculaires
ATE345793T1 (de) 2001-09-21 2006-12-15 Schering Corp Behandlung von xanthom mittels azetidinon- derivate als hemmer der sterol absorption
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
WO2004043456A1 (fr) 2002-11-06 2004-05-27 Schering Corporation Inhibiteurs d'absorption du cholesterol pour le traitement de la demyelination
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
JP2006519869A (ja) 2003-03-07 2006-08-31 シェーリング　コーポレイション 置換アゼチジノン化合物、置換アゼチジノン化合物を調製するためのプロセス、それらの処方物および使用
ES2318274T3 (es) 2003-03-07 2009-05-01 Schering Corporation Compuestos de azetidinona sustituida, formulaciones y uso de los mismos para el tratamiento de hipercolesterolemia.
ATE406364T1 (de) 2003-03-07 2008-09-15 Schering Corp Substituierte azetidinon-derivate, deren pharmazeutische formulierungen und deren verwendung zur behandlung von hypercholesterolemia

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Publication number Priority date Publication date Assignee Title
CA2042526A1 (fr) * 1990-06-11 1991-12-12 Adeoye Y. Olukotun Methode permettant de prevenir une deuxieme crise cardiaque a l'aide d'un inhibiteur de la hmg coa-reductase
US5622985A (en) * 1990-06-11 1997-04-22 Bristol-Myers Squibb Company Method for preventing a second heart attack employing an HMG CoA reductase inhibitor
CA2070149A1 (fr) * 1991-06-04 1992-12-05 Stephen J. Boccuzzi Inhibiteurs de la reductase hmg-coa utilises pour la prevention de la restenose suivant une angioplastie coronarienne
US6369103B1 (en) * 1994-01-18 2002-04-09 Bristol-Myers Squibb Company Method for preventing or reducing risk of onset of cardiovascular events employing an HMG CoA reductase inhibitor

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WO1999009967B1 (fr) 1999-07-08
CA2300165A1 (fr) 1999-03-04
WO1999009967A3 (fr) 1999-05-20
EP1007019A2 (fr) 2000-06-14
AU9115398A (en) 1999-03-16

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