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WO1999030706A1 - Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine - Google Patents

Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine Download PDF

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Publication number
WO1999030706A1
WO1999030706A1 PCT/US1998/023480 US9823480W WO9930706A1 WO 1999030706 A1 WO1999030706 A1 WO 1999030706A1 US 9823480 W US9823480 W US 9823480W WO 9930706 A1 WO9930706 A1 WO 9930706A1
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Prior art keywords
pharmaceutically acceptable
statin
pharmaceutical composition
kit
acceptable salt
Prior art date
Application number
PCT/US1998/023480
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English (en)
Inventor
Charles Larry Bisgaier
Roger Schofield Newton
Randy Ranjee Ramharack
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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
Priority to KR1020007006370A priority Critical patent/KR20010033017A/ko
Priority to HU0100349A priority patent/HUP0100349A3/hu
Priority to NZ502874A priority patent/NZ502874A/en
Priority to PL98343851A priority patent/PL343851A1/xx
Priority to CA002299397A priority patent/CA2299397A1/fr
Priority to JP2000538689A priority patent/JP2003524582A/ja
Priority to BR9813539-2A priority patent/BR9813539A/pt
Priority to EP98956562A priority patent/EP1037623A1/fr
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to IL13436498A priority patent/IL134364A0/xx
Priority to AU13060/99A priority patent/AU1306099A/en
Publication of WO1999030706A1 publication Critical patent/WO1999030706A1/fr
Priority to IS5385A priority patent/IS5385A/is
Priority to NO20002965A priority patent/NO20002965D0/no
Priority to AU2003244047A priority patent/AU2003244047A1/en

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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
    • A61K31/335—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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/365—Lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

  • This invention concerns a combination of a statin compound, which is known to cause a reduction in plasma levels of low-density lipoproteins (LDL) cholesterol, and a compound which inhibits the formation of lipoprotein (a),
  • Lp(a) which is a modified form of LDL, but which are unaffected by statins.
  • the combination is useful for treating vascular disorders and diabetes mellitus.
  • statins which are compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase, the enzyme responsible for catalyzing the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the cholesterol biosynthetic pathway.
  • HMG-CoA 3-hydroxy-3-methylglutaryl- coenzyme A
  • LDL low density lipoprotein
  • Lp(a) lipoprotein(a)
  • High levels of Lp(a) are now believed to be detrimental and can lead to cardiovascular diseases, and is one of the major risk factors leading to death from heart disease.
  • vascular diseases such as coronary heart disease, stroke, and even peripheral vascular disease, remain a leading cause of death and disability throughout the world, the need continues to develop new and improved treatments, as well as agents that will actually prevent the formation of these diseases.
  • Lp(a) inhibitors are the retinoids, as described in U.S. Patent 5,489,611 incorporated herein by reference.
  • This invention provides a pharmaceutical composition comprised of an effective amount of a statin and an effective amount of an Lp(a) inhibitor. More particularly, one embodiment of the invention is a combination of a statin with an Lp(a) inhibitor which is a retinoid.
  • the combinations of this invention can also employ the pharmaceutically acceptable salts of the respective active components.
  • Preferred retinoids are those described in U.S. Patent 5,489,611. Especially preferred compositions employ 9-cis-retinoic acid or 13-cis-retinoic acid. Also preferred are trans-retinal and trans-retinol, as well as 13-cis-retinol, 13-cis- retinal, 9-cis-retinol, and 9-cis-retinal.
  • Lp(a) inhibitors are aminophosphonates of the Formula I
  • ⁇ l and X ⁇ independently are hydrogen, straight or branched Cj-Cg alkyl and Cj-Cg alkoxy, hydroxy, or nitro;
  • X ⁇ is hydrogen or C1-C4 alkyl; or X 3 O, together with one of X ⁇ or X ⁇ is an alkylidene dioxy ring having from 1 to 4 carbon atoms;
  • Ri and R ⁇ independently are hydrogen, or straight or branched Cj-Cg alkyl
  • Z is hydrogen, straight or branched Cj-Cg alkyl, an aryl group Ar, or
  • R 3 CO where R 3 is C1-C4 alkyl or perfluoro C1-C4 alkyl
  • k is an integer from 2 to 4
  • m is 0 or an integer from 1 to 5
  • X ⁇ , X°, identical or different are H, a straight or branched alkyl or alkoxy groups from 1 to 8 carbon atoms, a hydroxy, trifluoromethyl, nitro, amino, dimethylamino, diethylamino group, a halogen atom (F, CI, Br, I), YA and ⁇ 5 may form an alkylidendioxy ring having from 1 to 4 carbon atoms
  • X ⁇ is H or CH3
  • R is a straight or branched alkyl group having from 1 to 6 carbon atoms, an aryl or arylalkyl group from 6 to 9 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • a preferred composition employs an aminophosphonate of the Formula II
  • Lp(a) inhibitors are diazo aniline derivatives, compounds of Formula III
  • Ri and R2 independently are hydrogen or straight or branched Cj-Cg alkyl, or taken together with the nitrogen to which they are attached complete a 5- to 7-membered ring, optionally substituted with C ⁇ -Cg alkyl or C j-Cg alkoxy;
  • R 3 is C ⁇ -C alkyl, Cj-Cg alkoxy, hydroxy, halo, nitro, perfluoroalkyl, amino, Cj-Cg alkyl or di-C ⁇ -C6 alkyl amino, or cyano;
  • Ar is phenyl optionally substituted by carboxyl, C ⁇ -C alkoxycarbonyl, cyano, CONH 2 , SO 2 NH 2 , Cj-Cg alkyl, Cj-Cg alkoxy, hydroxy, halo, nitro, amino, C ⁇ -Cg alkyl or di-Cj-Cg alkylamino, or C j -Cg arylamino.
  • compositions preferably will contain compounds of Formula III such as:
  • Typical statins to be employed in combination with the compound of Formula I include atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, lovastatin, dalvastatin, and fluindostatin.
  • the statins can be employed as pharmaceutically acceptable salts, for example, atorvastatin calcium.
  • a particularly preferred composition of this invention utilizes a retinoid together with a statin selected from atorvastatin calcium, pravastatin sodium, simvastatin, lovastatin, and cerivastatin. The most preferred composition employs the compound of Formula III with atorvastatin calcium.
  • the invention provides a method for lowering Lp(a), plasma triglycerides, very low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, and apolipoprotein B.
  • VLDL very low-density lipoprotein
  • the invention additionally provides a method for elevating plasma HDL cholesterol, apolipoprotein A-I, and apolipoprotein E.
  • the invention also provides a method for treating and preventing noninsulin-dependent diabetes mellitus by increasing insulin sensitivity comprising administering a combination of this invention.
  • an Lp(a) inhibitor is any compound which is effective at reducing Lp(a) in a mammal.
  • the Lp(a) inhibitors as used herein are compounds such as those described in U.S. Patent 5,489,611 and 5,424,303, both incorporated herein by reference.
  • the compounds can be the free acid or a salt form.
  • the other active component of the combinations of this invention is a statin.
  • statin where used in the specification and the appendant claims, is synonymous with the terms "3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor” and "HMG-CoA reductase inhibitor.” These three terms are used interchangeably throughout the specification and appendant claims. As the synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-
  • Coenzyme A reductase and, as such, are effective in lowering the level of blood plasma cholesterol.
  • Statins and pharmaceutically acceptable salts thereof are particularly useful in lowering low-density lipoprotein cholesterol (LDL-C) levels in mammals, and particularly in humans.
  • the HMG-CoA reductase inhibitors suitable for use herein include, but are not limited to, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, or pharmaceutically acceptable salts thereof.
  • atorvastatin calcium is a particularly preferred statin to be employed in the present combination. See U.S. Patent 5,273,995 incorporated herein by reference.
  • the statins disclosed herein are prepared by methods well-known to those skilled in the art. Specifically, simvastatin may be prepared according to the method disclosed in U.S. Patent 4,444,784, which is incorporated herein by reference. Pravastatin may be prepared according to the method disclosed in U.S. Patent 4,346,227, which is incorporated herein by reference. Cerivastatin may be prepared according to the method disclosed in U.S. Patent 5,502,199, which is incorporated herein by reference. Cerivastatin may alternatively be prepared according to the method disclosed in European Patent Application Publication No.
  • Mevastatin may be prepared according to the method disclosed in U.S. Patent 3,983,140, which is incorporated herein by reference.
  • Velostatin may be prepared according to the methods disclosed in U.S. Patent 4,448,784 and U.S.
  • Fluvastatin may be prepared according to the method disclosed in U.S. Patent 4,739,073, which is incorporated herein by reference.
  • Compactin may be prepared according to the method disclosed in U.S. Patent 4,804,770, which is incorporated herein by reference.
  • Lovastatin may be prepared according to the method disclosed in U.S.
  • Dalvastatin maybe prepared according to the method disclosed in European Patent Application Publication No. 738510 A2. Fluindostatin may be prepared according to the method disclosed in European Patent Application Publication No. 363934 Al. Dihydrocompactin may be prepared according to the method disclosed in U.S.
  • Patent 4,450,171 which is incorporated herein by reference.
  • statins contain either a free carboxylic acid or a free amine group as part of the chemical structure.
  • certain statins within the scope of this invention contain lactone moieties, which exist in equilibrium with the free carboxylic acid form. These lactones can be maintained as carboxylates by preparing pharmaceutically acceptable salts of the lactone.
  • this invention includes pharmaceutically acceptable salts of those carboxylic acids or amine groups.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • salts are intended to define but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino- 2-hydroxymethyl-l,3-propanediol) and procaine.
  • alkali metal salts e.g., sodium and potassium
  • alkaline earth metal salts e.g., calcium and magnesium
  • aluminum salts e.g., ammonium salts
  • salts with organic amines such as benzathine (N,N'-dibenzylethylene
  • pharmaceutically acceptable add addition salts is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
  • the pharmaceutically acceptable cationic salts of statins containing free carboxylic acids may be readily prepared by reacting the free acid form of the statin with an appropriate base, usually one equivalent, in a co-solvent.
  • Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine, and tromethamine.
  • the salt is isolated by concentration to dryness or by addition of a non-solvent.
  • salts are preferably prepared by mixing a solution of the acid with a solution of a different salt of the cation (sodium or potassium ethylhexanoate, magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the desired cationic salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
  • a solvent e.g., ethyl acetate
  • the pharmaceutically acceptable acid addition salts of statins containing free amine groups may be readily prepared by reacting the free base form of the statin with the appropriate acid.
  • the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate), or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed.
  • a monobasic acid e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate
  • the hydrogen form of a dibasic acid e.g., the hydrogen sulfate, the succinate
  • salts as the sulfate, the hemisuccinate, the hydrogen phosphate, or the phosphate
  • the appropriate and exact chemical equivalents of acid will generally be used.
  • the free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
  • statins of the instant invention and the pharmaceutically acceptable salts of the statins of the instant invention may also occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
  • Lp(a) inhibitors for example, the retinoids.
  • the pharmaceutical combinations and methods of this invention are all adapted to therapeutic use as agents in the prevention and treatment of atherosclerosis, angina pectoris, and a condition characterized by the presence of both hypertension and hyperlipidemia in mammals, particularly humans.
  • compositions of the present invention as medical agents in the treatment of atherosclerosis in mammals (e.g., humans) is demonstrated by the activity of the compounds of this invention in conventional assays and in a clinical protocol such as that described below. Effect of an Lp(a) Inhibitor and a Statin, Alone and in Combination, on the Treatment of Atherosclerosis
  • This study is a prospective randomized evaluation of the effect of a combination of 9-cis-retinoic acid or a pharmaceutically acceptable salt thereof and a statin on the progression/regression of coronary and carotid artery disease.
  • the study is used to show that a combination of 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt and a statin is effective in slowing or arresting the progression or causing regression of existing coronary artery disease (CAD) as evidenced by changes in coronary angiography or carotid ultrasound, in subjects with established disease.
  • CAD coronary artery disease
  • This study is an angiographic documentation of coronary artery disease carried out as a double-blind, placebo-controlled trial of a minimum of about 500 subjects and preferably of about 780 to about 1200 subjects. It is especially preferred to study about 1200 subjects in this study. Subjects are admitted into the study after satisfying certain entry criteria set forth below.
  • Subjects accepted for entry into this trial must satisfy certain criteria. Thus, the subject must be an adult, either male or female, aged 18 to 80 years of age in whom coronary angiography is clinically indicated. Subjects will have angiographic presence of a significant focal lesion such as 30% to 50% on subsequent evaluation by quantitative coronary angiography (QCA) in a minimum of one segment (non-PTCA, non-bypassed, or non-MI vessel) that is judged not likely to require intervention over the next 3 years. It is required that the segments undergoing analysis have not been interfered with. Since percutaneous transluminal cardiac angioplasty (PTCA) interferes with segments by the insertion of a balloon catheter, non-PTCA segments are required for analysis.
  • PTCA percutaneous transluminal cardiac angioplasty
  • segment to be analyzed have not suffered a thrombotic event, such as a myocardial infarct (MI).
  • MI myocardial infarct
  • Segments that will be analyzed include: left main, proximal, mid and distal left anterior descending, first and second diagonal branch, proximal and distal left circumflex, first or largest space obtuse marginal, proximal, mid and distal right coronary artery.
  • Subjects will have an ejection fraction of greater than 30% determined by catheterization or radionuclide ventriculography or ECHO cardiogram at the time of the qualifying angiogram or within the previous
  • the study is carried out at multiple sites.
  • subjects undergo quantitative coronary angiography as well as B-mode carotid artery ultrasonography and assessment of carotid arterial compliance at designated testing centers. This establishes baselines for each subject.
  • subjects are randomized to receive the compound of 9-cis-retinoic acid (200 mg) and placebo or a statin (dose is dependent upon the particular statin used; however, generally 80 mg will be used at first) and placebo or 9-cis-retinoic acid (200 mg) and a statin (80 mg).
  • the free base form or other salt forms of 9-cis-retinoic acid or the free base form or other salt forms of the statin may be used in this invention. Calculation of the dosage amount for these other forms of the statin and 9-cis-retinoic acid is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The amount of 9-cis-retinoic acid may be varied as required. Generally, a subject will start out taking 200 mg, and the amount will be titrated down to as little as 50 mg as determined by the clinical physician. The amount of the statin will similarly be titrated down from 80 mg if it is determined by the physician to be in the best interests of the subject.
  • B-mode carotid ultrasound assessment of carotid artery atherosclerosis and compliance are performed at regular intervals throughout the study. Generally, 6-month intervals are suitable. Typically this assessment is performed using B-mode ultrasound equipment. However, a person skilled in the art may use other methods of performing this assessment.
  • Coronary angiography is performed at the conclusion of the 1- to 3 -year treatment period.
  • the baseline and posttreatment angiograms and the intervening carotid artery B-mode ultrasonograms are evaluated for new lesions or progression of existing atherosclerotic lesions.
  • Arterial compliance measurements are assessed for changes from baseline and over the 6-month evaluation periods.
  • the primary objective of this study is to show that the combination of carboxyalkylether or a pharmaceutically acceptable acid addition salt and a statin reduces the progression of atherosclerotic lesions as measured by quantitative coronary angiography (QCA) in subjects with clinical coronary artery disease.
  • QCA measures the opening in the lumen of the arteries measured.
  • the primary endpoint of the study is the change in the average mean segment diameter of the coronary artery tree.
  • the diameter of an arterial segment is measured at various portions along the length of that segment.
  • the average diameter of that segment is then determined.
  • the average of all segment averages is determined to arrive at the average mean segment diameter.
  • the mean segment diameter of subjects taking a statin and 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt will decline more slowly, will be halted completely, or there will be an increase in the mean segment diameter.
  • the secondary objective of this study is that the combination of carboxyalkylether or a pharmaceutically acceptable acid addition salt and a statin reduces the rate of progression of atherosclerosis in the carotid arteries as measured by the slope of the maximum intimal-medial thickness measurements averaged over 12 separate wall segments (Mean Max) as a function of time, more than does compound III or a pharmaceutically acceptable acid addition salt or a statin alone.
  • the intimal-medial thickness of subjects taking a statin and compound III or a pharmaceutically acceptable salt thereof will increase more slowly, will cease to increase, or will decrease.
  • This study is a double-blind, parallel-arm, randomized study to show the effectiveness of 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt thereof and a statin given in combination in the treatment of symptomatic angina.
  • Subjects are males or females between 18 and 80 years of age with a history of typical chest pain associated with one of the following objective evidences of cardiac ischemia: (1) stress test segment elevation of about one millimeter or more from the ECG; (2) positive treadmill stress test; (3) new wall motion abnormality on ultrasound; or (4) coronary angiogram with a significant qualifying stenosis. Generally a stenosis of about 30% to 50% is considered to be significant.
  • Each subject is evaluated for about 10 to 32 weeks. At least 10 weeks are generally required to complete the study. Sufficient subjects are used in this screen to ensure that about 200 to 800 subjects and preferably about 400 subjects are evaluated to complete the study. Subjects are screened for compliance with the entry criteria, set forth below, during a 4-week run-in phase. After the screening criteria are met, subjects are washed out from their current anti-anginal medication and stabilized on a long acting nitrate such as nitroglycerine, isosorbide-
  • washout when used in connection with this screen, means the withdrawal of current anti-anginal medication so that substantially all of said medication is eliminated from the body of the subject.
  • a period of 8 weeks is preferably allowed for both the washout period and for the establishment of the subject on stable doses of said nitrate.
  • Subjects having one or two attacks of angina per week while on stable doses of long acting nitrate are generally permitted to skip the washout phase.
  • the subjects enter the randomization phase provided the subjects continue to have either one or two angina attacks per week.
  • the subjects are randomly placed into one of the four arms of the study set forth below.
  • ECG electrocardiogram
  • subjects in compliance with the entry criteria undergo 24-hour ambulatory electrocardiogram (ECG) such as Holter monitoring, exercise stress testing such as a treadmill, and evaluation of myocardial perfusion using photon emission tomography (PET) scanning to establish a baseline for each subject.
  • ECG electrocardiogram
  • PET photon emission tomography
  • the speed of the treadmill and the gradient of the treadmill can be controlled by a technician.
  • the speed of the treadmill and the angle of the gradient are generally increased during the test.
  • the time intervals between each speed and gradient increase is generally determined using a modified Bruce Protocol.
  • the person conducting the test will evaluate the subject using the tests described. Successful treatment will yield fewer instances of ischemic events as detected by ECG, will allow the subject to exercise longer or at a higher intensity level on the treadmill or to exercise without pain on the treadmill, or will yield better perfusion or fewer perfusion defects on PET.
  • the utility of the compounds of the present invention as medical agents in the treatment of hypertension and hyperlipidemia in mammals (e.g., humans) suffering from a combination of hypertension and hyperlipidemia is demonstrated by the activity of the compounds of this invention in conventional assays and the clinical protocol described below.
  • This study is a double-blind, parallel-arm, randomized study to show the effectiveness of carboxyalkylether or a pharmaceutically acceptable acid addition salt thereof and a statin given in combination in controlling both hypertension and hyperlipidemia in subjects who have mild, moderate, or severe hypertension and hyperlipidemia.
  • Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are used in this screen to ensure that about 400 to 800 subjects are evaluated to complete the study.
  • Subjects are male or female adults between 18 and 80 years of age having both hyperlipidemia and hypertension. The presence of hyperlipidemia is evidenced by evaluation of the LDL cholesterol level of the subject relative to certain positive risk factors. If the subject has no coronary heart disease (CHD) and has less than two positive risk factors, then the subject is considered to have hyperlipidemia, which requires drug therapy if the LDL of the subject is > 190 mg/dL. If the subject has no CHD and has two or more positive risk factors, then the subject is considered to have hyperlipidemia, which requires drug therapy if the LDL of the subject is > 160 mg/dL. If the subject has CHD, then the subject is considered to have hyperlipidemia if the LDL of the subject is
  • Positive risk factors include: (1) male over 45, (2) female over 55 wherein said female is not undergoing hormone replacement therapy (HRT), (3) family history of premature cardiovascular disease, (4) the subject is a current smoker, (5) the subject has diabetes, (6) an HDL of less than 45 mg/dL, and (7) the subject has hypertension.
  • An HDL of >60 mg/dL is considered a negative risk factor and will offset one of the above mentioned positive risk factors.
  • BP diastolic blood pressure
  • Subjects are screened for compliance with the entry criteria set forth above. After all screening criteria are met, subjects are washed out from their current antihypertensive and lipid lowering medication and are placed on the NCEP ATP II Step 1 diet.
  • NCEP ATP II adult treatment panel, 2nd revision
  • Step 1 diet sets forth the amount of saturated and unsaturated fat which can be consumed as a proportion of the total caloric intake.
  • the term "washed out", where used in connection with this screen, means the withdrawal of current antihypertensive and lipid lowering medication so that substantially all of said medication is eliminated from the body of the subject. Newly diagnosed subjects generally remain untreated until the test begins. These subjects are also placed on the NCEP Step 1 diet. After the 4-week washout and diet stabilization period, subjects undergo the following baseline investigations: (1) blood pressure and (2) fasting lipid screen. The fasting lipid screen determines baseline lipid levels in the fasting state of a subject. Generally, the subject abstains from food for
  • a fixed dose of 9-cis-retinoic acid generally about 25 to 200 mg
  • a statin generally about 2.5 mg to about 160 mg
  • the free base form or other salt forms of 9-cis-retinoic acid or the free base form or other salt forms of the statin may be used in this invention. Calculation of the dosage amount for these other forms of the statin and 9-cis-retinoic acid is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • Subjects remain on these doses for a minimum of 6 weeks, and generally for no more than 8 weeks.
  • the subjects return to the testing center at the conclusion of the 6 to 8 weeks so that the baseline evaluations can be repeated.
  • the blood pressure of the subject at the conclusion of the study is compared with the blood pressure of the subject upon entry.
  • the lipid screen measures the total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, very low-density lipoprotein (VLDL) and other components of the lipid profile of the subject. Improvements in the values obtained after treatment relative to pretreatment values indicate the utility of the drug combination.
  • This study is a double-blind, parallel-arm, randomized study to demonstrate the effectiveness of carboxyalkylether or a pharmaceutically acceptable acid addition salt and a statin given in combination in reducing the overall calculated risk of future events in subjects who are at risk for having future cardiovascular events.
  • This risk is calculated by using the Framingham Risk Equation.
  • a subject is considered to be at risk of having a future cardiovascular event if that subject is more than one standard deviation above the mean as calculated by the Framingham Risk Equation.
  • the study is used to evaluate the efficacy of a fixed combination of carboxylalkyl ether or a pharmaceutically acceptable acid addition salt and a statin in controlling cardiovascular risk by controlling both hypertension and hyperlipidemia in patients who have both mild to moderate hypertension and hyperlipidemia. Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks.
  • Subjects included in the study are male or female adult subjects between 18 and 80 years of age with a baseline 5-year risk, which risk is above the median for said subject's age and sex, as defined by the Framingham
  • Heart Study which is an ongoing prospective study of adult men and women showing that certain risk factors can be used to predict the development of coronary heart disease.
  • the age, sex, systolic and diastolic blood pressure, smoking habit, presence or absence of carbohydrate intolerance, presence or absence of left ventricular hypertrophy, serum cholesterol, and HDL of more than one standard deviation above the norm for the Framingham Population are all evaluated in determining whether a patient is at risk for adverse cardiac event.
  • the values for the risk factors are inserted into the Framingham Risk Equation and calculated to determine whether a subject is at risk for a future cardiovascular event. Subjects are screened for compliance with the entry criteria set forth above.
  • ATP II Step 1 diet After the 4-week washout and diet stabilization period, subjects undergo the following baseline investigations: (1) blood pressure; (2) fasting; (3) lipid screen; (4) glucose tolerance test; (5) ECG; and (6) cardiac ultrasound. These tests are carried out using standard procedures well-known to persons skilled in the art.
  • the ECG and the cardiac ultrasound are generally used to measure the presence or absence of left ventricular hypertrophy.
  • a fixed dose of 9-cis-retinoic acid about 25 to 200 mg
  • a statin about 2.5 mg to about 160 mg
  • the new values are entered into the Framingham Risk Equation to determine whether the subject has a lower, greater, or no change in the risk of future cardiovascular event.
  • dosage amounts and other dosage amounts set forth elsewhere in this specification and in the appendant claims are for an average human subject having a weight of about 65 kg to about 70 g.
  • the skilled practitioner will readily be able to determine the dosage amount required for a subject whose weight falls outside the 65 to 70 kg range, based upon the medical history of the subject and the presence of diseases, e.g., diabetes, in the subject.
  • All doses set forth herein, and in the appendant claims, are daily doses.
  • the Lp(a) inhibitor is generally administered in a dosage of about 25 mg to about 500 mg.
  • 9-cis-retinoic acid is administered in a dosage of about 5 mg to about 100 mg.
  • the free base form or other salt forms of 9-cis-retinoic acid may be used in this invention. Calculation of the dosage amount for these other forms of or the free base form or other salt forms of La(a) inhibitors is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • statins are administered in the following dosage amounts:
  • Simvastatin generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 40 mg;
  • Pravastatin generally about 2.5 mg to about 160 mg and preferably about
  • Cerivastatin generally about 25 ⁇ g to about 5 mg and preferably about 1 mg to about 3.2 mg;
  • Fluvastatin generally about 2.5 mg to about 160 mg and preferably about 20 mg to about 80 mg;
  • Lovastatin generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 80 mg; and Atorvastatin, generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 80 mg.
  • statins may be used in this invention. Calculation of the dosage amount for these other forms of or the free base form or other salt forms said statins is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • the compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier or diluent.
  • the compounds of this invention can be administered either individually or together in any conventional oral, parenteral, or transdermal dosage form.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes.
  • compositions of a similar type are also employed as fillers in soft- and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
  • the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents, and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin, and various like combinations thereof.
  • the combinations of this invention may also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • a controlled release formulation such as a slow release or a fast release formulation.
  • Such controlled release formulations of the combination of this invention may be prepared using methods well-known to those skilled in the art. The method of administration will be determined by the attendant physician or other person skilled in the art after an evaluation of the subject's condition and requirements.
  • the generally preferred formulation of atorvastatin calcium is Lipitor® as described in U.S. Patent 5,686,104, incorporated herein by reference.
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • compositions according to the invention may contain 0.1% to 95% of the compound(s) of this invention, preferably 1% to 70%.
  • the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the condition or disease of the subject being treated.
  • the kit includes two separate pharmaceutical compositions: a carboxyalkylether or a pharmaceutically acceptable acid addition salt thereof and a statin or a pharmaceutically acceptable salt thereof.
  • the kit includes container means for containing the separate compositions such as a divided bottle or a divided foil packet; however, the separate compositions may also be contained within a single, undivided container.
  • the kit includes directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

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  • Urology & Nephrology (AREA)
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Abstract

L'invention concerne une composition pharmaceutique renfermant un inhibiteur de lipoprotéine (a) et une statine, qui a un effet inhibiteur sur la HMG-CoA réductase. Ce type de composition est utile pour le traitement des maladies vasculaires.
PCT/US1998/023480 1997-12-12 1998-11-04 Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine WO1999030706A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
BR9813539-2A BR9813539A (pt) 1997-12-12 1998-11-04 Combinações de inibidor de lp(a) e estatina anti-hiperlipidêmicas
NZ502874A NZ502874A (en) 1997-12-12 1998-11-04 Antihyperlipidemic statin-lp(a) inhibitor combinations
PL98343851A PL343851A1 (en) 1997-12-12 1998-11-04 Antihyperlipidemic statin-lp(a) inhibitor combinations
CA002299397A CA2299397A1 (fr) 1997-12-12 1998-11-04 Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine
JP2000538689A JP2003524582A (ja) 1997-12-12 1998-11-04 抗高脂血症性スタチン−Ｌｐ（ａ）阻害剤配合物
KR1020007006370A KR20010033017A (ko) 1997-12-12 1998-11-04 과지질혈증 치료제인 스타틴-ＬＰ(ａ) 억제제의 병용 제제
AU13060/99A AU1306099A (en) 1997-12-12 1998-11-04 Antihyperlipidemic statin-lp(a) inhibitor combinations
EP98956562A EP1037623A1 (fr) 1997-12-12 1998-11-04 Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine
IL13436498A IL134364A0 (en) 1997-12-12 1998-11-04 ANTIHYPERLIPIDEMIC STATIN-LP (a) INHIBITOR COMBINATIONS
HU0100349A HUP0100349A3 (en) 1997-12-12 1998-11-04 Pharmaceutical compositions containing antihyperlipidemic statin-lp(a) inhibitor
IS5385A IS5385A (is) 1997-12-12 2000-02-25 Statin-LP(A)-tálma-lyfjablöndur við fitudreyra
NO20002965A NO20002965D0 (no) 1997-12-12 2000-06-09 Antihyperlipidemisk statin-LP(a) inhibitor kombinasjoner
AU2003244047A AU2003244047A1 (en) 1997-12-12 2003-08-29 Antihyperlipidemic stain-Lp(a) inhibitor combinations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6943297P 1997-12-12 1997-12-12
US60/069,432 1997-12-12

Publications (1)

Publication Number Publication Date
WO1999030706A1 true WO1999030706A1 (fr) 1999-06-24

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PCT/US1998/023480 WO1999030706A1 (fr) 1997-12-12 1998-11-04 Compositions antilipemiques combinant un inhibiteur de lipoproteine (a) et une statine

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EP (1) EP1037623A1 (fr)
JP (1) JP2003524582A (fr)
KR (1) KR20010033017A (fr)
AU (2) AU1306099A (fr)
BR (1) BR9813539A (fr)
CA (1) CA2299397A1 (fr)
HU (1) HUP0100349A3 (fr)
IL (1) IL134364A0 (fr)
IS (1) IS5385A (fr)
NO (1) NO20002965D0 (fr)
NZ (1) NZ502874A (fr)
PL (1) PL343851A1 (fr)
WO (1) WO1999030706A1 (fr)
ZA (1) ZA9811349B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051078A1 (fr) * 2000-01-10 2001-07-19 Amylin Pharmaceuticals, Inc. Utilisation d'exendines et d'agonistes de ces dernieres pour moduler les taux de triglycerides et pour traiter la dyslipidemie
EP1275388A1 (fr) * 2000-02-10 2003-01-15 Takeda Chemical Industries, Ltd. Inhibiteurs de tnf-alpha
EP1586644A2 (fr) * 1999-08-09 2005-10-19 Universite Catholique De Louvain Medicament pour la prévention et/ou la traitement des cardiopathies ischémiques, des acrosyndromes, et le développement des tumeurs, et dans la cicatrisations des plaies
US7138375B2 (en) 1997-01-07 2006-11-21 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for lowering plasma lipid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013801A1 (fr) * 1992-01-17 1993-07-22 The Procter & Gamble Company Traitement de l'arteriosclerose
WO1993016690A1 (fr) * 1992-02-25 1993-09-02 Warner-Lambert Company Compositions cytoprotectrices contenant du pyruvate et des antioxydants
EP0738510A2 (fr) * 1995-04-20 1996-10-23 L'oreal Utilisation d'un inhibiteur d'hmg coenzyme A reductase pour lutter contre le vieillissement de la peau
WO1997014403A1 (fr) * 1995-10-18 1997-04-24 Mary Kay Inc. Traitements de rupture de barriere pour peaux presentant une structure deterioree

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2016467A1 (fr) * 1989-06-05 1990-12-05 Martin Eisman Methode de traitement de l'atherosclerose des vaisseaux peripheriques a l'aide d'un inhibiteur de l'hmg coa reductase et (ou) d'un inhibiteur de la squalene synthetase
US5648387A (en) * 1995-03-24 1997-07-15 Warner-Lambert Company Carboxyalkylethers, formulations, and treatment of vascular diseases
AU732465B2 (en) * 1996-04-17 2001-04-26 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardiovascular disease
NZ503982A (en) * 1997-12-12 2002-03-28 Warner Lambert Co Statin-carboxyalkylether combinations useful for treating vascular disorders and diabetes mellitus

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013801A1 (fr) * 1992-01-17 1993-07-22 The Procter & Gamble Company Traitement de l'arteriosclerose
WO1993016690A1 (fr) * 1992-02-25 1993-09-02 Warner-Lambert Company Compositions cytoprotectrices contenant du pyruvate et des antioxydants
EP0738510A2 (fr) * 1995-04-20 1996-10-23 L'oreal Utilisation d'un inhibiteur d'hmg coenzyme A reductase pour lutter contre le vieillissement de la peau
WO1997014403A1 (fr) * 1995-10-18 1997-04-24 Mary Kay Inc. Traitements de rupture de barriere pour peaux presentant une structure deterioree

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DIMITROULAKOS ET AL: "HMG-CoA Reductase Mediates the Biological Effects of Retinoc Acid on Human Neuroblastoma Cells: Lovastatin Specifically Targets P-Glycoprotein-Expressing Cells", NATURE MEDICINE, vol. 2, no. 3, March 1996 (1996-03-01), pages 326 - 333, XP002103070 *
GLUECK ET AL: "Gemfibrozil-Lovastatin Therapy for Primary Hyperlipoproteinemia", THE AMERICAN JOURNAL OF CARDIOLOGY, vol. 70, no. 1, 1 July 1992 (1992-07-01), pages 1 - 9, XP002103067 *
HAAG ET AL: "Lovastatin Inhibits Receptor-Stimulated Ca++-Influx in Retinoic Acid Differentiated U937 and HL-60 Cells", CELLULAR SIGNALLING, vol. 6, no. 7, 1994, pages 835 - 742, XP002103068 *
KRAUSE ET AL: "Emerging Therapies in Atherosclerosis", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 4/5, 1995, pages 353 - 387, XP002103072 *
RAMHARACK ET AL: "Retinoids Inhibit Primary Cynomolgus Monkey Hepatocyte Lipoprotein(a) Levels", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 238, no. 1, 8 September 1997 (1997-09-08), pages 48 - 52, XP002103071 *
RAMIRES ET AL: "Effect of Gemfibrozil versus Lovastatin on Increased Serum Lipoprotein(a) Levels of Patients with Hypercholesterolemia", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 48, no. 2, 1995, pages 115 - 120, XP002103069 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7138375B2 (en) 1997-01-07 2006-11-21 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for lowering plasma lipid
EP1586644A2 (fr) * 1999-08-09 2005-10-19 Universite Catholique De Louvain Medicament pour la prévention et/ou la traitement des cardiopathies ischémiques, des acrosyndromes, et le développement des tumeurs, et dans la cicatrisations des plaies
EP1586644A3 (fr) * 1999-08-09 2008-06-25 Universite Catholique De Louvain Medicament pour la prévention et/ou la traitement des cardiopathies ischémiques, des acrosyndromes, et le développement des tumeurs, et dans la cicatrisations des plaies
WO2001051078A1 (fr) * 2000-01-10 2001-07-19 Amylin Pharmaceuticals, Inc. Utilisation d'exendines et d'agonistes de ces dernieres pour moduler les taux de triglycerides et pour traiter la dyslipidemie
JP2003519667A (ja) * 2000-01-10 2003-06-24 アミリン・ファーマシューティカルズ，インコーポレイテッド トリグリセリドレベルの調節および脂質異常血症の治療のためのエキセンジンおよびそのアゴニストの使用
EP1275388A1 (fr) * 2000-02-10 2003-01-15 Takeda Chemical Industries, Ltd. Inhibiteurs de tnf-alpha
EP1275388A4 (fr) * 2000-02-10 2003-11-26 Takeda Chemical Industries Ltd Inhibiteurs de tnf-alpha

Also Published As

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PL343851A1 (en) 2001-09-10
AU2003244047A1 (en) 2003-09-25
AU1306099A (en) 1999-07-05
CA2299397A1 (fr) 1999-06-24
IL134364A0 (en) 2001-04-30
NO20002965L (no) 2000-06-09
ZA9811349B (en) 1999-06-14
HUP0100349A3 (en) 2002-02-28
HUP0100349A2 (hu) 2001-07-30
NZ502874A (en) 2004-03-26
JP2003524582A (ja) 2003-08-19
BR9813539A (pt) 2000-10-10
NO20002965D0 (no) 2000-06-09
EP1037623A1 (fr) 2000-09-27
IS5385A (is) 2000-02-25
KR20010033017A (ko) 2001-04-25

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