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WO1997038694A1 - Therapie d'association destinee a reduire les risques lies a une maladie cardio-vasculaire - Google Patents

Therapie d'association destinee a reduire les risques lies a une maladie cardio-vasculaire Download PDF

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Publication number
WO1997038694A1
WO1997038694A1 PCT/US1997/006127 US9706127W WO9738694A1 WO 1997038694 A1 WO1997038694 A1 WO 1997038694A1 US 9706127 W US9706127 W US 9706127W WO 9738694 A1 WO9738694 A1 WO 9738694A1
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WIPO (PCT)
Prior art keywords
hmg
inhibitor
pharmaceutically acceptable
vitamin
disease
Prior art date
Application number
PCT/US1997/006127
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English (en)
Inventor
Jonathan A. Tobert
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 GBGB9612082.9A external-priority patent/GB9612082D0/en
Priority claimed from GBGB9616804.2A external-priority patent/GB9616804D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97918595A priority Critical patent/EP0904082A4/fr
Priority to JP9537264A priority patent/JP2000508659A/ja
Priority to AU26665/97A priority patent/AU732465B2/en
Publication of WO1997038694A1 publication Critical patent/WO1997038694A1/fr

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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

  • the instant invention involves a combination therapy comprising the administration of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) and folic acid or a pharmaceutically acceptable salt or ester thereof for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • HMG-CoA RI 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • folic acid or folic acid or a pharmaceutically acceptable salt or ester thereof for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics.
  • the fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used.
  • Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable.
  • lovastatin the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects.
  • folic acid is a vitamin
  • relatively inexpensive folic acid is a vitamin
  • the active agents can be readily combined in a single tablet, capsule or other dosage form having the same or similar size as the inhibitor of HMG-CoA reductase alone. This would provide patient convenience, an important consideration especially in patients who already have coronary heart disease, as such patients generally have several different drugs to take.
  • the instant invention involves a novel combination therapy comprised of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof.
  • One object of the instant invention is to administer the above-described combination therapy to people who do not yet show clinical signs of atherosclerosis, but who are at risk of developing atherosclerosis and associated diseases.
  • Clinical manifestations of atherosclerosis include atherosclerotic cardiovascular disease such as coronary heart disease (also known as ischemic heart disease), cerebrovascular disease, and peripheral vessel disease.
  • the instant invention provides methods for preventing or reducing the risk of developing atherosclerotic cardiovascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above- described combination therapy to said at-risk persons.
  • a second object of the instant invention is to provide the above-described combination therapy to people who have clinical signs of atherosclerosis.
  • the instant invention provides methods for halting or slowing the progression of atherosclerotic cardiovascular disease, coronary heart disease, ischemic heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above-described combination therapy to said persons who have clinically manifest atherosclerotic disease.
  • a third object of the instant invention involves the above- described methods further comprising the administration of one or more additional active agents, for example, a bile acid sequestrant, cholesterol abso ⁇ tion inhibitor, squalene synthase inhibitor, and/or niacin, either in separate or combined dosage formulations.
  • a fourth object is to provide pharmaceutical compositions which can be used in the above-described methods. Additional objects will be evident from the following detailed description.
  • the instant invention provides methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a therapeutically effective amount of an HMG-CoA RI in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • the combination comprised of an HMG-CoA RI and folic acid or folate may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication.
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular W 97/3 94
  • Atherosclerotic disease event as used herein is intended to encompasses coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease event are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event comprising the administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or folate to a person at risk of developing atherosclerotic disease.
  • the instant combination therapy can also be administered to a person who already has atherosclerotic disease for preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event.
  • Persons to be treated with the instant combination therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • HDL high density lipoprotein
  • People who are identified as having one or more of the above-noted risk factors are intended to be included in the group of people considered at risk for developing atherosclerotic disease. People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®), simvastatin (ZOCOR®), pravastatin (PRAVACHOL®), fluvastatin (LESCOL®), atorvastatin and rivastatin (also known as cerivastatin).
  • lovastatin MEVACOR®
  • simvastatin ZOCOR®
  • pravastatin PRAVACHOL®
  • fluvastatin LESCOL®
  • atorvastatin also known as cerivastatin
  • the structural formulas of these and additional 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).
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts and esters is included within the scope of this invention.
  • HMG-CoA reductase 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.
  • the HMG-CoA RI is selected from lovastatin and simvastatin.
  • Folic acid or a pharmaceutically acceptable salt or ester thereof is administered in combination with the HMG-CoA reductase inhibitor.
  • Pharmaceutically acceptable salts of folic acid are well known to those skilled in the art and include, for example, the sodium salt and the methylglucamine salt.
  • the acid moiety also lends itself to the preparation of pharmaceutically acceptable esters, and such esters are likewise included in the scope of the invention.
  • the term "folate" is used herein to refer to the pharmaceutically acceptable salts and esters of folic acid.
  • pharmaceutically acceptable 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.
  • 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.
  • the instant method involves the administration of an HMG- CoA reductase inhibitor in combination with folic acid or a folate.
  • This combination therapy includes administration of a single pharmaceutical dosage formulation which contains both the HMG-CoA reductase inhibitor and the folic acid or folate, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • the HMG-CoA reductase inhibitor and the folic acid or folate can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially.
  • HMG-CoA reductase inhibitor and the folic acid or folate be co-administered concurrently on a once-a-day dosing schedule.
  • a single dosage formulation comprised of both an HMG-CoA reductase inhibitor and the folic acid or folate is preferred.
  • a single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients who already have coronary heart disease and may be in need of multiple medications.
  • terapéuticaally effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response 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 in combination with folic acid or folate is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the O 97/38694 PC17US97/06127
  • HMG-CoA RI's and for folic acid are well known in the art, since several HMG-CoA RI's and nutritional supplements containing folic acid are marketed in the U.S.
  • the daily dosage amounts of the HMG-CoA reductase inhibitor are intended to 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).
  • 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, 80 mg and 160 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 therapeutically effective amount of folic acid to be used in the instant method is intended to be a dosage amount sufficient to reduce the plasma level of homocysteine below the pre ⁇ treatment plasma level of homocysteine in the person receiving the combination therapy.
  • dosage amounts of folic acid are described in the PDR. For example, see at page 119 of the 1996 PDR the heading "Folic Acid" and the reference pages cited therein.
  • the daily dosage amount of folic acid or folate employed in the instant combination therapy can be from about 0.1 to 20 mg/day.
  • the dosage is from about 0.1 to 10 mg/day, more particularly from about 0.1 to 5 mg/day, and most particularly from about 1 to 5 mg/day, based on the free acid weight.
  • the daily dosage amount of folic acid or folate may be selected from 1 mg, 2 mg and 5 mg, based on the free acid weight.
  • Additional active agents may be combined with the HMG-CoA RI and folic acid or folate in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration.
  • One or more additional active agents may be administered with the HMG-CoA RI and folic acid or folate.
  • the additional active agent or agents can be cholesterol lowering compounds.
  • HMG-CoA synthase inhibitors examples include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol abso ⁇ tion inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin Bi2 (also known as cyanocobalamin); aspirin; beta-blockers; and anti-oxidant vitamins such as vitamin C and E and beta carotene.
  • ACAT cholesterol acyltransferase
  • probucol n
  • HMG-CoA synthase inhibitors include: the beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564, 4,816,477, 4,847,271 , and 4,751 ,237; the beta lactam derivatives disclosed in U.S. 4,983,597 and the substituted oxacyclopropane analogues disclosed in European Patent Publication EP O 41 1 703.
  • the squalene synthetase inhibitors suitable for use herein include, but are not limited to, those disclosed by Biller et al., J. Med. Chem., 1988 Vol. 31 , No. 10, pp. 1869-1871 , including isoprenoid (phosphinylmethyl)-phosphonates such as those of the formula
  • R 1 is:
  • squalene synthetase inhibitors including the triacids thereof, triesters thereof and tripotassium and trisodium salts thereof as well as other squalene synthetase inhibitors disclosed in pending U.S. Patent No. 4,871,721 and 4,924,024 and in Biller et al, J. Med.Chem., 1988, Vol. 31, No. 10, pp. 1869 to 1871.
  • other squalene synthetase inhibitors suitable for use herein include the te ⁇ enoid pyrophosphates disclosed by P. Ortiz de Montellano et al., J. Med.
  • the benzodiazepine squalene synthase inhibitors described in EP O 567 026 to Takeda Chemical Industries and the quinuclidinyl squalene synthase inhibitors described in PCT publications WO 94/03451 , WO 93/091 15, WO 93/21 183, WO 93/21 184, WO 93/24486, and U.S. 5,135,935, may be co- administered with the HMG-CoA RI plus folic acid or folate combination of the present invention.
  • squalene epoxidase inhibitors are disclosed in European Patent Publication EP O 318 860 and in Japanese Patent Publication J02 169-571 A.
  • LDL-receptor gene inducer molecules are disclosed in U.S. Patent No. 5, 182,298.
  • bile acid sequestrants which may be employed in the present method include cholestyramine, colestipol, and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalidej and those disclosed in W095/34585 to Geltex Pharmaceuticals, Inc. and EP 0 622 078 assigned to Hisamitsu Pharmaceutical Co., Inc.
  • cholesterol abso ⁇ tion inhibitors which may be employed in the present method include those described in WO 95/18143 and WO 95/18144 both assigned to Pfizer Inc., and WO 94/17038, WO 95/08532 and WO 93/02048 each assigned to Schering Co ⁇ .
  • the additional active agents described above which may be employed along with the HMG-CoA RI and folic acid or folate combination therapy can be used, for example, in amounts as indicated in the PDR or in amounts as indicated in the reference disclosures, as appropriate.
  • compositions for both HMG-CoA RI's and for folic acid or folates are well-known to those skilled in the art, as evidenced by the information provided in the 1996 PDR.
  • Methods for preparing various pharmaceutical compositions comprising the combination of an HMG-CoA RI and folic acid or folate are likewise well known to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active agents employed in the instant combination 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.
  • the instant invention includes the use of both oral rapid-release and time-controlled release pharmaceutical formulations. Oral formulations are preferred.
  • the HMG-CoA RI and the folic acid or folate may be formulated together with or without an additional active agent, and are typically administered in admixture with suitable 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.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • 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 ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be inco ⁇ orated 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 agents of the present method may be administered in divided doses, for example two or three times daily, a single daily dose of each of the HMG-CoA RI and the folic acid or folate is preferred, with a single daily dose of both agents in a single pharmaceutical composition being most preferred.
  • a therapeutically effective amount of an HMG- CoA RI and folic acid or a pharmaceutically acceptable salt or ester thereof can be used together for the preparation of a medicament useful for preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of an atherosclerotic disease event.
  • the medicament may be comprised of folic acid or folate in combination with about 1 mg to 200 mg of an HMG-CoA RI, or more particularly about 5 mg to 160 mg of the HMG-CoA RI.
  • HMG-CoA RI More specific amounts of HMG-CoA RI which may be used in the medicament preparation include 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg, as well as sub-milligram amounts of HMG-CoA RI's which have sufficient potency at such levels.
  • the medicament may be comprised of an HMG-CoA RI in combination with about 0.1 to 20 mg of folic acid or folate.
  • the amount of folic acid or folate used in the preparation of the medicament may be from about 0.1 to 10 mg, or more particularly 7/38694 PC17US97/06127
  • the medicament may be comprised of 1 mg, 2 mg or 5 mg of folic acid or folate, based on the free acid weight.
  • the above-described medicament may also be prepared with one or more additional active agents such as an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an ACAT inhibitor, probucol, niacin, a fibrate, a cholesterol abso ⁇ tion inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B6 and the pharmaceutically acceptable salts thereof, vitamin Bi2, aspirin, beta-blockers.
  • vitamin C vitamin E and beta carotene.
  • An example of an oral dosage formulation comprising both an HMG-CoA RI and folic acid which is suitable for use in practicing the instant method invention is as follows:
  • All the ingredients except magnesium stearate are blended together in a suitable mixer.
  • the powder mixture is then granulated with adequate quantities of granulating solvent(s).
  • the wet granulated mass is dried in a suitable dryer.
  • the dried granulation is sized through a suitable screen.
  • the sized granulation is mixed with magnesium stearate before tableting.
  • the tablets may be coated if deemed necessary.
  • Additional ingredients that may be added to the above include suitable color and mixtures of colors.

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Abstract

La présente invention porte sur des procédés visant à éviter ou é réduire le risque de développer une athérosclérose, ainsi qu'à enrayer ou à freiner l'évolution de la maladie athéroscléreuse lorsqu'elle a été constatée cliniquement. Ces procédés consistent noramment à administrer à une personne susceptible de développer une athérosclérose ou ayant déjà une athérosclérose une dose efficace en termes thérapeutiques d'un inhibiteur de réductase de 3-hydroxy-3-méthylglutaryl coenzyme A (HMG-CoA RI), combiné avec de l'acide folique ou avec un sel ou un ester de celui-ci acceptable sur le plan pharmaceutique.
PCT/US1997/006127 1996-04-17 1997-04-14 Therapie d'association destinee a reduire les risques lies a une maladie cardio-vasculaire WO1997038694A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97918595A EP0904082A4 (fr) 1996-04-17 1997-04-14 Therapie d'association destinee a reduire les risques lies a une maladie cardio-vasculaire
JP9537264A JP2000508659A (ja) 1996-04-17 1997-04-14 心血管疾患関連の危険性を低減する組み合わせ療法
AU26665/97A AU732465B2 (en) 1996-04-17 1997-04-14 Combination therapy for reducing the risks associated with cardiovascular disease

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US1568996P 1996-04-17 1996-04-17
US60/015,689 1996-04-17
GBGB9612082.9A GB9612082D0 (en) 1996-06-10 1996-06-10 Combination therapy for reducing the risks associated with cardiovascular disease
GB9612082.9 1996-06-10
US2097796P 1996-06-24 1996-06-24
US60/020,977 1996-06-24
GB9616804.2 1996-08-09
GBGB9616804.2A GB9616804D0 (en) 1996-08-09 1996-08-09 Combination therapy for reducing the risks associated with cardiovascular disease

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WO1997038694A1 true WO1997038694A1 (fr) 1997-10-23

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JP (1) JP2000508659A (fr)
AU (1) AU732465B2 (fr)
CA (1) CA2251972A1 (fr)
WO (1) WO1997038694A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2336534A (en) * 1998-04-24 1999-10-27 Alec James Coppen Anti-depressant - Folic Acid Combination
WO1999015159A3 (fr) * 1997-09-24 2000-02-17 Nova Molecular Inc Methodes permettant d'augmenter les taux d'apolipoproteine dans le traitement de maladies neurodegeneratives
WO2001074394A1 (fr) * 2000-04-03 2001-10-11 Astrazeneca Ab Nouvelle combinaison d'un betabloquant et d'un hypocholesterolemiant
GB2361186A (en) * 2000-04-10 2001-10-17 Nicholas J Wald Pharmaceutical formulation for the prevention of cardiovascular disease
WO2001076632A1 (fr) * 2000-04-10 2001-10-18 Wald Nicholas J Formulation destinee a la prevention de maladies cardio-vasculaires
WO2001097751A3 (fr) * 2000-06-22 2002-03-28 Astrazeneca Ab Nouvelle formulation
WO2002034261A1 (fr) * 2000-10-23 2002-05-02 Sankyo Company, Limited Compositions hypocholesterolemiantes
WO2002047683A1 (fr) * 2000-12-14 2002-06-20 Sankyo Company, Limited Composition ameliorant les lipides dans le sang
WO2002047682A1 (fr) * 2000-12-14 2002-06-20 Sankyo Company, Limited Composition ameliorant les lipides sanguins
WO2002049640A1 (fr) * 2000-12-18 2002-06-27 Sankyo Company, Limited Composition servant a faire baisser le taux de triglycerides
EP1071403A4 (fr) * 1998-03-18 2002-09-18 Bristol Myers Squibb Co Composition pharmaceutique contenant une statine et de l'aspirine
EP0946178A4 (fr) * 1996-09-18 2003-05-07 Merck & Co Inc Traitement combine destine a reduire les risques de maladies cardio-vasculaires
JP2003524582A (ja) * 1997-12-12 2003-08-19 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー 抗高脂血症性スタチン−Ｌｐ（ａ）阻害剤配合物
WO2004006919A1 (fr) * 2002-07-11 2004-01-22 Sankyo Company, Limited Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
WO2004012740A1 (fr) * 2002-08-02 2004-02-12 Sankyo Company, Limited Composition medicamenteuse contenant un inhibiteur de hmg-coa reductase
WO2005060975A1 (fr) * 2003-12-23 2005-07-07 Medicure International Inc. Polytherapies mettant en oeuvre une composition renfermant un inhibiteur de l'hmg coa reductase et un compose relatif a la vitamine b6
US6916849B2 (en) 2000-10-23 2005-07-12 Sankyo Company, Limited Compositions for improving lipid content in the blood
US6998422B2 (en) 2000-11-07 2006-02-14 Sankyo Company, Limited Lipid peroxide-lowering compositions
US7037934B2 (en) 2000-12-14 2006-05-02 Sankyo Company, Limited Blood lipid ameliorant composition
WO2006072172A1 (fr) * 2005-01-05 2006-07-13 Medicure International Inc. Composes et techniques de regulation des niveaux de triglyceride
EP1339429A4 (fr) * 2000-11-29 2007-03-14 Smithkline Beecham Corp Composition contenant des statines et du calcium destinee a ameliorer la sante cardiovasculaire
WO2008036846A3 (fr) * 2006-09-22 2008-11-13 Braincells Inc Modulation induite par hmg-coa-réductase de la neurogenèse
EP1732605A4 (fr) * 2004-03-29 2009-05-27 Wyeth Corp Complements nutritionnels mineraux multivitamines
EP3175849A1 (fr) 2013-06-06 2017-06-07 Ferrer Internacional, S.A. Formulation orale pour le traitement de maladies cardiovasculaires

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WO1999015159A3 (fr) * 1997-09-24 2000-02-17 Nova Molecular Inc Methodes permettant d'augmenter les taux d'apolipoproteine dans le traitement de maladies neurodegeneratives
US6274603B1 (en) 1997-09-24 2001-08-14 Mcgill University Methods for increasing ApoE levels for the treatment of neurodegenerative disease
JP2003524582A (ja) * 1997-12-12 2003-08-19 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー 抗高脂血症性スタチン−Ｌｐ（ａ）阻害剤配合物
EP1071403A4 (fr) * 1998-03-18 2002-09-18 Bristol Myers Squibb Co Composition pharmaceutique contenant une statine et de l'aspirine
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WO2001074394A1 (fr) * 2000-04-03 2001-10-11 Astrazeneca Ab Nouvelle combinaison d'un betabloquant et d'un hypocholesterolemiant
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WO2001076632A1 (fr) * 2000-04-10 2001-10-18 Wald Nicholas J Formulation destinee a la prevention de maladies cardio-vasculaires
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US8470868B2 (en) 2000-04-10 2013-06-25 Nicholas J. Wald Formulation for the prevention of cardiovascular disease
WO2001097751A3 (fr) * 2000-06-22 2002-03-28 Astrazeneca Ab Nouvelle formulation
RU2271802C2 (ru) * 2000-06-22 2006-03-20 Астразенека Аб Применение фармацевтического препарата, содержащего бета-блокатор
WO2002034261A1 (fr) * 2000-10-23 2002-05-02 Sankyo Company, Limited Compositions hypocholesterolemiantes
US6916849B2 (en) 2000-10-23 2005-07-12 Sankyo Company, Limited Compositions for improving lipid content in the blood
US6998422B2 (en) 2000-11-07 2006-02-14 Sankyo Company, Limited Lipid peroxide-lowering compositions
EP1339429A4 (fr) * 2000-11-29 2007-03-14 Smithkline Beecham Corp Composition contenant des statines et du calcium destinee a ameliorer la sante cardiovasculaire
WO2002047683A1 (fr) * 2000-12-14 2002-06-20 Sankyo Company, Limited Composition ameliorant les lipides dans le sang
WO2002047682A1 (fr) * 2000-12-14 2002-06-20 Sankyo Company, Limited Composition ameliorant les lipides sanguins
US7012067B2 (en) 2000-12-14 2006-03-14 Sankyo Company, Limited Blood lipid ameliorant composition
CN100369605C (zh) * 2000-12-14 2008-02-20 三共株式会社 血液脂质改善剂组合物
US7037934B2 (en) 2000-12-14 2006-05-02 Sankyo Company, Limited Blood lipid ameliorant composition
CN1307990C (zh) * 2000-12-18 2007-04-04 三共株式会社 甘油三酸酯降低剂组合物
WO2002049640A1 (fr) * 2000-12-18 2002-06-27 Sankyo Company, Limited Composition servant a faire baisser le taux de triglycerides
CN100341509C (zh) * 2002-07-11 2007-10-10 三共株式会社 用于改善血液中脂质或降低血液中高半胱氨酸的药物组合物
WO2004006919A1 (fr) * 2002-07-11 2004-01-22 Sankyo Company, Limited Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
WO2004012740A1 (fr) * 2002-08-02 2004-02-12 Sankyo Company, Limited Composition medicamenteuse contenant un inhibiteur de hmg-coa reductase
WO2005060975A1 (fr) * 2003-12-23 2005-07-07 Medicure International Inc. Polytherapies mettant en oeuvre une composition renfermant un inhibiteur de l'hmg coa reductase et un compose relatif a la vitamine b6
EP1732605A4 (fr) * 2004-03-29 2009-05-27 Wyeth Corp Complements nutritionnels mineraux multivitamines
AU2005228421B2 (en) * 2004-03-29 2011-07-21 Pf Consumer Healthcare 1 Llc Multi-vitamin and mineral nutritional supplements
AU2005228421B8 (en) * 2004-03-29 2011-11-17 Pf Consumer Healthcare 1 Llc Multi-vitamin and mineral nutritional supplements
WO2006072172A1 (fr) * 2005-01-05 2006-07-13 Medicure International Inc. Composes et techniques de regulation des niveaux de triglyceride
WO2008036846A3 (fr) * 2006-09-22 2008-11-13 Braincells Inc Modulation induite par hmg-coa-réductase de la neurogenèse
EP3175849A1 (fr) 2013-06-06 2017-06-07 Ferrer Internacional, S.A. Formulation orale pour le traitement de maladies cardiovasculaires
MD4475C1 (ro) * 2013-06-06 2017-11-30 Ferrer Internacional, S.A. Utilizare a unei formulări cu administrare orală pentru tratamentul bolilor cardiovasculare

Also Published As

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EP0904082A1 (fr) 1999-03-31
EP0904082A4 (fr) 2001-09-26
CA2251972A1 (fr) 1997-10-23
AU2666597A (en) 1997-11-07
AU732465B2 (en) 2001-04-26
JP2000508659A (ja) 2000-07-11

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