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WO1998001116A1 - Therapie contre l'hyperlipemie combinee - Google Patents

Therapie contre l'hyperlipemie combinee Download PDF

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Publication number
WO1998001116A1
WO1998001116A1 PCT/US1997/012426 US9712426W WO9801116A1 WO 1998001116 A1 WO1998001116 A1 WO 1998001116A1 US 9712426 W US9712426 W US 9712426W WO 9801116 A1 WO9801116 A1 WO 9801116A1
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WIPO (PCT)
Prior art keywords
simvastatin
per day
cholesterol
administered
pharmaceutically acceptable
Prior art date
Application number
PCT/US1997/012426
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English (en)
Inventor
Yale B. Mitchel
Michael R. Melino
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 GBGB9617898.3A external-priority patent/GB9617898D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU36672/97A priority Critical patent/AU3667297A/en
Publication of WO1998001116A1 publication Critical patent/WO1998001116A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-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
    • A61K31/335—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 the administration of at least 160 mg per day of simvastatin, which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, or a pharmaceutically acceptable salt or ester thereof, for treating combined hyperlipidemia and for lowering the level of very low density lipoprotein (VLDL) in mammals, especially humans.
  • simvastatin which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, or a pharmaceutically acceptable salt or ester thereof
  • Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. There are five classifications of lipoproteins based on their degree of density: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL), and high density lipoproteins (HDL). Triglycerides are the major lipids transported in the blood; between 70 and 150 gm enter and leave the plasma daily compared to 1 to 2 gm of cholesterol or phospholipid.
  • Hyperlipidemia is generally subdivided into the conditions of hypercholesterolemia and hypertriglyceridemia.
  • the existence of elevated LDL chholesterol levels along with hypertriglyceridemia is known as combined hyperlipidemia.
  • the initial treatment for both conditions is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when lipid-lowering goals are not met by diet and exercise alone.
  • cholesterol lowering drugs were limited essentially to the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), probucol, and the fibrates such as clofibrate, fenofibrate, and gemfibrizol.
  • bile acid sequestrants cholesterol esteramine and colestipol
  • nicotinic acid niacin
  • probucol the fibrates
  • fibrates such as clofibrate, fenofibrate, and gemfibrizol.
  • Substantial reductions in LDL cholesterol accompanied by increases in HDL cholesterol could be achieved by the combination of a lipid-lowering diet and a bile acid sequestrant, with or without the addition of nicotinic acid.
  • 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 particularly for the treatment of hypertriglyceridemia.
  • 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 MEVACOR®
  • 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 levels with very few adverse effects.
  • HMG-CoA reductase inhibitors such as simvastatin (ZOCOR®), pravastatin (PRAVACHOL®), and fluvastatin (LESCOL®).
  • ZOCOR® simvastatin
  • PRAVACHOL® pravastatin
  • LESCOL® fluvastatin
  • lovastatin and simvastatin both members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries.
  • Simvastatin has also been shown to reduce the risk of coronary heart disease events, and 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 some evidence for a reduction in cerebrovascular events.
  • Hypertriglyceridemia is a condition in which there is an excessive amount of triglyceride (generally greater than about 300mg/dl) in the plasma. Triglyceride lowering is recognized as a desirable therapeutic goal since elevated triglyceride levels may play a role in atherogenesis and the development of coronary heart disease.
  • severe hypertriglyceridemia > lOOOmg/dl is associated with chylomicronemia and causes acute pancreatitis. Severe elevations in chylomicrons directly induce pancreatitis, which can be prevented by triglyceride reduction.
  • Elevated triglyceride levels are commonly seen in Type IV and Type V hyperlipoproteinemic patients and are associated with obesity, diabetes, beta -blocker therapy and chronic renal failure. It is therefore desirable to provide a method for reducing plasma triglycerides in patients with combined hyperlipidemia.
  • the present invention provides a novel method for treating combined hyperlipidemia and lowering VLDL comprising the administration of at least 160 mg/day of simvastatin to a patient in need of such treatment. It has been dicovered that a daily dosage of 160 mg of simvastatin reduces triglyceride and VLDL levels to a surprisingly greater degree than would have been expected based on the reductions previously seen with lower daily dosage amounts of the drug, as well as effectively reducing elevated LDL cholesterol levels.
  • One object of the instant invention is to provide a novel method for treating hypertriglyceridemia in a mammal with combined hyperlipidemia comprising the administration of a therapeutically effective amount of at least 160 mg per day of simvastatin or a pharmaceutically acceptable salt or ester thereof to the mammal in need of such treatment.
  • a related object is to provide a novel method for treating combined hyperlipidemia comprising the administration of a therapeutically effective amount of at least 160 mg per day of simvastatin or a pharmaceutically acceptable salt or ester thereof to a mammal in need of such treatment.
  • Another object of the instant invention is to provide a novel method for lowering very low density lipoprotein cholesterol levels in a mammal with combined hyperlipidemia comprising the administration of a therapeutically effective amount of at least 160 mg per day of simvastatin or a pharmaceutically acceptable salt or ester thereof to a mammal in need of such treatment.
  • Another 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 absorption inhibitor, squalene synthase inhibitor, folic acid, and/or niacin, either in separate or combined dosage formulations.
  • additional active agents for example, a bile acid sequestrant, cholesterol absorption inhibitor, squalene synthase inhibitor, folic acid, and/or niacin, either in separate or combined dosage formulations.
  • a further 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.
  • Simvastatin shown below, is currently marketed worldwide under a variety of trademark names in unit dosage amounts of up to 40 mg.
  • the current maximal recommended dose of simvastatin is 40 mg daily.
  • Simvastatin To evaluate the effectiveness of extending the dosage range of simvastatin up to 80 mg and 160 mg once daily, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) ⁇ 350 mg/dl were randomized to simvastatin at doses of 40, 80 and 160 mg once daily in a 26 week, double-blind, three period, complete block cross-over study. Each active treatment period was 6 weeks in duration with intervening 2 week wash-out periods. Median reductions from baseline in LDL cholesterol were 41 %, 47%, and 53% in the 40, 80 and 160 mg groups, respectively. The corresponding reductions in plasma triglycerides were 21 , 23 and 33%. HDL cholesterol increased by 6-8% in each group.
  • Subjects Men, post-menopausal women, and women highly unlikely to conceive, aged 21 to 70 with an LDL cholesterol of 160 to 250 mg/dl and fasting triglycerides £ 350 mg/dl were eligible.
  • Major exclusion criteria were myocardial infarction or a coronary revascularization procedure within the past 6 months, acute coronary insufficiency, uncontrolled systemic hypertension, secondary hypercholesterolemia, diabetes mellitus, serum creatinine >1.6 mg/dl, underlying hepatic disease (or elevations of liver transaminases above the normal limit), creatine kinase > 1.5 times the upper normal limit, history of alcohol abuse, body weight > 50% above ideal, or previously demonstrated intolerance to hydroxymethylglutaryl coenzyme A reductase inhibitors.
  • the protocol was approved by the institutional review board at each site and written informed consent was obtained from all patients.
  • Study design This was a 26-week, multicenter, double-blind, three- period crossover study in 7 US lipid clinics. Patients not currently complying with a National Cholesterol Education Program Step 1 diet or better were provided with detailed instruction with reinforcement throughout the study. Patients already on lipid lowering agents underwent at least a 6- week washout before randomization. Those patients meeting the eligibility requirements after a 4-week placebo and diet treatment period were assigned to simvastatin 40 mg, 80 mg, or 160 mg daily in random sequence each for 6 weeks, with a 2-week placebo washout period between treatments. There were 1 1 study visits at weeks -4, -1 , 1 , 3, 6, 8, 1 1 , 14, 16, 19, and 22.
  • Study Therapy Simvastatin (ZOCOR®, Merck & Co, Inc, New Jersey) 40, 80 and 160 mg once daily were administered as a combination of 20 and 40 mg tablets. Patients were given 3 bottles containing active drug or matching placebo, with instructions to take 2 tablets from each bottle every evening. The study was thus double- blind.
  • Simvastatin ZOCOR®, Merck & Co, Inc, New Jersey
  • Study procedures A physical examination was performed at randomization and at the conclusion of the study. Vital signs, blood count and routine serum chemistry and urinalysis were obtained at each visit. Morning blood samples after a 12 hour fast were drawn for lipoproteins and cortisol, and in men only testosterone, follicle stimulating hormone, and leutinizing hormone, at the start of the study (week 1) and at the end of each 6-week treatment period (weeks 6, 14 and 22). Adverse events, defined as new symptoms or signs or a worsening of a previous condition, were noted at each visit.
  • LDL- and VLDL- cholesterol levels were determined by ultracentrifugation (see "Lipid RCP., Manual of Laboratory Operations: Lipid and Lipoprotein Analysis," Washington, DC: US Dept. of Health Education and Welfare, Publication NIH. 1982; 75:628.)
  • LDL-cholesterol was obtained by subtracting HDL-cholesterol from the d> 1.006 g/ml fraction cholesterol.
  • Very low density lipoprotein (VLDL)-cholesterol level was obtained by subtracting the d> 1.006 g/ml cholesterol from the total cholesterol.
  • Apolipoproteins A-I and B analyses were performed using competitive enzyme-linked immunoabsorption assays (see Stein E, et al., "Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Multicenter Group I," Arch Intern Med. 1990; 750(2):341-5; Stein E, et al., "Development and evaluation of a competitive ELISA for Lp(a)" (abstr), Clin Chem.
  • Serum concentrations of follicle stimulating hormone and luteinizing hormone were assayed using a competitive binding assay with I 125 radiolabelled hormone using an anti-hormone antibody (see Santer S, et al., "A model for validation of radioimmunoassay kit reagents: measurement of follitropin and lutropin in blood and urine," Clin Chem. 1981; 27: 1892-1895; and Kubasik N, et al., "Evaluation of direct solid phase radioimmunoassay for progesterone, useful for monitoring luteal function," Clin Chem.
  • Plasma drug levels were obtained by analyzing hydroxymethylglutaryl coenzyme A reductase inhibitory activity at the Department of Drug Metabolism, Merck Research Laboratories, West Point, PA (see Alberts A, et al., "Mevinolin. A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol lowering agent," Proc Natl Acad Sci. 1980; 77:3957-3961; and Stubbs RJ, et al., "Comparison of plasma profiles of lovastatin, simvastatin, and pravastatin in the dog," Drug Invest. 1990; 2 (Suppl. 2): 18-28).
  • the mean age of the cohort was 52 and 40% were women. Seven patients dropped out before the end of Period 1 and therefore contributed no efficacy data to the analysis. Individual patient percent changes showed a clearly skewed distribution for LDL cholesterol, especially at 80 and 160 mg. Therefore the median was used as the principal summary statistic for change from baseline.
  • Table 1 summarizes the lipid and lipoprotein effects of simvastatin from the study outlined above.
  • Table 1 shows median percent change from baseline in lipids and apolipoproteins, with p values for the difference between 40 and 80 mg and between 80 and 160 mg. Baseline values are mean (SD); percent changes are median (interquartile range).
  • Abbreviations are as follows: Total-C is total cholesterol; LDL-C is low density lipoprotein cholesterol; Apo B is apolipopoprotein B; HDL-C is high density lipoprotein cholesterol; Apo Al is apolipoprotein Al; VLDL-C is very low density lipoprotein cholesterol; TG is triglycerides.
  • VLDL-C 37 (24) -32 0.34 -33 0.03 -42
  • Doubling the dose of any inhibitor of 3-hydroxy-3- methylglutaryl coenzyme A reductase generally provides an additional absolute reduction in LDL cholesterol of about 6% relative to the original baseline, at least up to the currently maximal recommended doses (see Illingworth DR, Tobert JA, "A review of clinical trials comparing HMG-CoA reductase inhibitors," Clin Ther. 1994; 76(3):366-85; and Pedersen TR, Tobert JA, "Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal," Drug Safety. 1996; 7 : 1 1 -24). This continues to apply to simvastatin at least up to 160 mg.
  • simvastatin produced median changes in LDL cholesterol of -41 %, -47%, and -53% respectively. Changes in total cholesterol and apolipopoprotein B were commensurate with those for LDL cholesterol. The changes in HDL cholesterol and apolipoprotein Al were essentially the same at all three doses.
  • the 160 mg daily dose of simvastatin produced substantially greater reductions in VLDL cholesterol than what would have been expected from the VLDL cholesterol changes obtained with the 40 mg and 80 mg doses, as well as compared to the median percent changes seen at all doses for total cholesterol, LDL cholesterol, HDL cholesterol, apolipopoprotein B and apolipoprotein A
  • the median change in VLDL cholesterol was virtually identical at the 40 mg (-32%) and 80 mg (-33%) doses, but dropped dramatically to -42% at the 160 mg dose.
  • the 160 mg daily dose of simvastatin produced substantially greater reductions in triglycerides than what would have been expected from the triglyceride changes obtained with the 40 mg and 80 mg doses, as well as compared to the median percent changes seen at all doses for total cholesterol, LDL cholesterol, HDL cholesterol, apolipopoprotein B and apolipoprotein Al.
  • the median change in triglycerides was virtually identical at the 40 mg (-21) and 80 mg (-23%) doses, but dropped dramatically to -33% at the 160 mg dose.
  • the instant therapy may be prescribed to lower triglyceride levels and/or VLDL cholesterol in patients with combined hyperlipidemia when such lowering is deemed advisable within the educated discretion of the prescribing physician or other clinician.
  • the benefit of triglyceride and LDL reductions in these patients must be balanced against safety concerns when utilizing high doses of HMG CoA reductase inhibitors. This therapy would not be indicated in patients with severe hypertriglyceridemia (levels > 800 mg/dl) who are at risk of pancreatitis and in whom fibrates are appropriate therapy
  • Simvastatin and its pharmaceutically acceptable salts and esters are intended to be included within the scope of the instant invention.
  • Salt and ester derivatives can be made from the lactone ring- opened form of simvastatin.
  • pharmaceutically acceptable salts shall mean non-toxic salts of the compounds employed in this invention which can be prepared by reacting the lactone or free acid with a suitable organic or inorganic base.
  • Ester derivatives of simvastatin 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 term "therapeutically effective amount” is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of the mammal that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • mammal includes humans.
  • the dosage regimen utilizing simvastatin 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 route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective dosage amounts to be given to a person in need of the instant therapy.
  • the daily dosage amount of simvastatin used with the instant methods is 160 mg. or more, and preferably the daily dosage amount is 160 mg. administered orally.
  • simvastatin may be administered in divided doses, for example two, three or four times daily, a once per day dosing schedule is preferred.
  • the dosage amount may be given in a single oral dosage unit or in multiple oral dosage units.
  • a daily dosage amount of 160 mg may be administered with a single 160 mg tablet or with multiples of 40 or 80 mg tablets co-adminstered concurrently.
  • the instant invention includes the use of both oral rapid-release and time- controlled release pharmaceutical formulations.
  • One or more additional active agents may be combined with simvastatin in a single dosage formulation, or may be administered to the patient in separate dosage formulations, which allows for concurrent administration (i.e., co-administration at essentially the same time) or sequential administration (i.e., co- administration at separately staggered times).
  • the additional active agent or agents may be but are not limited to 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 absorption 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 HC1 salt; vitamin Bl2 (also known as cyanocobalamin); platelet aggregation inhibitors such as aspirin and fibrinogen receptor antagonists; beta-blockers; and anti-oxidant vitamins such as vitamin C and E and beta carotene.
  • ACAT cholesterol
  • 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 terpenoid 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 93/21183, 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 dihalidel and those disclosed in W095/34585 to Geltex Pharmaceuticals, Inc. and EP 0 622 078 assigned to Hisamitsu Pharmaceutical Co., Inc.
  • cholesterol absorption 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 Corp.
  • 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. 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.
  • simvastatin may be formulated together with or without an additional active agent, and is 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 incorporated into the mixture.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gal late, 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.
  • a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt or ester thereof can be used for the preparation of a medicament useful for treating hypertriglyceridemia and for lowering very low density lipoprotein levels in mammals, particularly humans.
  • the medicament may be comprised of 160 mg of simvastatin.
  • 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 absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B and the pharmaceutically acceptable salts thereof, vitamin Bl2, aspirin, beta-blockers, vitamin C, vitamin E and beta carotene.
  • 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 absorption inhibitor, a bile acid sequesterant, an LDL receptor inducer, vitamin B and the pharmaceutically acceptable salts thereof, vitamin Bl2, as

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Abstract

Cette invention concerne des procédés ainsi que des compositions pharmaceutiques qui permettent de traiter l'hyperlipémie combinée. Ces procédés et ces compositions permettent également d'abaisser les niveaux élevés de cholestérol à très faible densité en lipoprotéines chez les mammifères souffrant d'hyperlipémie combinée. Ce procédé consiste à administrer quotidiennement à un mammifère nécessitant un tel traitement, une quantité efficace sur le plan thérapeutique d'au moins 160 mg de simvastatine ou, encore, d'un sel ou d'un ester de cette dernière acceptable sur le plan pharmaceutique.
PCT/US1997/012426 1996-07-09 1997-07-03 Therapie contre l'hyperlipemie combinee WO1998001116A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36672/97A AU3667297A (en) 1996-07-09 1997-07-03 Therapy for combined hyperlipidemia

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US2142096P 1996-07-09 1996-07-09
US60/021,420 1996-07-09
GBGB9617898.3A GB9617898D0 (en) 1996-08-28 1996-08-28 Method for treating homozygous familial hypercholesterolemia
GB9617898.3 1996-08-28
US2935196P 1996-10-31 1996-10-31
US60/029,351 1996-10-31

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PCT/US1997/011792 WO1998001100A2 (fr) 1996-07-09 1997-07-03 Methode de traitement de l'hypercholesterolemie familiale homozygote
PCT/US1997/010867 WO1998001119A2 (fr) 1996-07-09 1997-07-03 Compositions pharmaceutiques

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PCT/US1997/010867 WO1998001119A2 (fr) 1996-07-09 1997-07-03 Compositions pharmaceutiques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030212996A1 (en) * 1996-02-08 2003-11-13 Wolzien Thomas R. System for interconnection of audio program data transmitted by radio to remote vehicle or individual with GPS location
WO2000018395A1 (fr) * 1998-09-30 2000-04-06 Warner-Lambert Company Procede pour empecher ou retarder la revascularisation par catheter
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
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ATE348649T1 (de) 2001-01-26 2007-01-15 Schering Corp Kombinationen von einem hemmer der sterol- absorption und einem ppar-aktivator zur behandlung von kardiovaskulären indikationen
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US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
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
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WO2003055991A1 (fr) * 2001-12-21 2003-07-10 Rigshospitalet Mobilisation de gametes et amelioration de la competence de developpement chez les mammiferes au moyen de l'inhibition de la biosynthese des sterols de novo et/ou de l'activation de la sortie des sterols
AR040588A1 (es) 2002-07-26 2005-04-13 Schering Corp Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa
CA2504878A1 (fr) 2002-11-06 2004-05-27 Schering Corporation Inhibiteurs d'absorption du cholesterol pour le traitement de la demyelination
US7192944B2 (en) 2003-03-07 2007-03-20 Schering Corp. Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
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.
ES2311806T3 (es) 2003-03-07 2009-02-16 Schering Corporation Compuesto de azetidinona sustituidos, fornulaciones y usos de los mismos para el tratamiento de hipercolesterolemia.
JOP20080381B1 (ar) 2007-08-23 2023-03-28 Amgen Inc بروتينات مرتبطة بمولدات مضادات تتفاعل مع بروبروتين كونفيرتاز سيتيليزين ككسين من النوع 9 (pcsk9)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806564A (en) * 1987-05-26 1989-02-21 Merck & Co., Inc. Antihypercholesterolemic beta-lactones

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4997849A (en) * 1989-06-23 1991-03-05 Merck & Co., Inc. Microbial transformation of simvastatin
US5393893A (en) * 1993-11-08 1995-02-28 Apotex, Inc. Process for producing simvastatin and analogs thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806564A (en) * 1987-05-26 1989-02-21 Merck & Co., Inc. Antihypercholesterolemic beta-lactones

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AU3667297A (en) 1998-02-02
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WO1998001100A3 (fr) 1998-02-12
WO1998001100A2 (fr) 1998-01-15
WO1998001119A2 (fr) 1998-01-15

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