WO1998001100A2 - Method for treating homozygous familial hypercholesterolemia - Google Patents
Method for treating homozygous familial hypercholesterolemia Download PDFInfo
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- WO1998001100A2 WO1998001100A2 PCT/US1997/011792 US9711792W WO9801100A2 WO 1998001100 A2 WO1998001100 A2 WO 1998001100A2 US 9711792 W US9711792 W US 9711792W WO 9801100 A2 WO9801100 A2 WO 9801100A2
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- Prior art keywords
- simvastatin
- day
- ldl
- familial hypercholesterolemia
- homozygous familial
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- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 title claims abstract description 18
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 14
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 25
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960002855 simvastatin Drugs 0.000 claims abstract description 24
- 238000009472 formulation Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000008214 LDL Cholesterol Methods 0.000 abstract description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 8
- 102000007330 LDL Lipoproteins Human genes 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 108010028554 LDL Cholesterol Proteins 0.000 description 6
- 108010023302 HDL Cholesterol Proteins 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108010001831 LDL receptors Proteins 0.000 description 3
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 3
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 2
- 239000004059 squalene synthase inhibitor Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 102000018616 Apolipoproteins B Human genes 0.000 description 1
- 108010027006 Apolipoproteins B Proteins 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 102000002284 Hydroxymethylglutaryl-CoA Synthase Human genes 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100030817 Liver carboxylesterase 1 Human genes 0.000 description 1
- 101710181187 Liver carboxylesterase 1 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 102000005782 Squalene Monooxygenase Human genes 0.000 description 1
- 108020003891 Squalene monooxygenase Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 229940096699 bile acid sequestrants Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021194 placebo diet Nutrition 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
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
- A61K31/335—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
- Homozygous familial hypercholesterolemia is a rare disorder characterized by the presence of two abnormal low density lipoprotein (LDL) receptor genes which results in the patient having dysfunctional LDL receptors. This results in severe hypercholesterolemia, particularly extreme elevations in LDL levels, and rapid development of coronary atherosclerosis and coronary heart disease in those who suffer with HFH. Most patients develop coronary disease in adolescence and usually do not survive beyond their teen-age years.
- LDL low density lipoprotein
- HMG-CoA reductase inhibitors such as compactin, lovastatin, simvastatin, pravastatin, etc., are believed to work by upregulating LDL receptor activity and increasing LDL removal from the blood. Since FH homozygotes do not have functional LDL receptors, this class of drugs was generally believed to be ineffective in these patients. Previous experience with HMG-CoA reductase inhibitors in FH homozygote children bore this out. For example, in J.
- LDL aphaeresis is a technique where plasma is removed from patients and run over columns either with an antibody to apo B or reagents to precipitate LDL. It is usually performed once every two weeks in this population with about a 70% reduction in LDL cholesterol immediately after the procedure, with levels returning to baseline at one week post- treatment. Both treatment options are associated with considerable morbidity and are in limited supply.
- atorvastatin a second-generation HMG-CoA reductase inhibitor, atorvastatin, has been shown to be useful for treating HFH.
- simvastatin (marketed in the U.S. under the trademark ZOCOR®) in doses above 40 mg per day can be used to treat patients suffering with HFH.
- the main object of the instant invention is to provide a method for treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment.
- a person in need of such treatment is one who has homozygous familial hypercholesterolemia. Additional objects will be evident from the following detailed description.
- simvastatin in daily dosages above 40 mg are useful for the treatment of HFH.
- the daily dosage is at least 80 mg, and more preferably, at least 160 mg.
- the compound may be administered in a single daily dose, or divided doses, for example two, three or four times daily.
- Simvastatin may also be administered in a sustained release formulation, for example employing the formulation described in U.S. Patent No. 5,366,738. Sustained release and daily divided dose administration is preferred.
- the following study results demonstrate the usefulness of simvastatin in the treatment of HFH.
- T-C total cholesterol
- LDL-C low density lipoprotein cholesterol
- TRIG triglyceride level
- HDL-C high density lipoprotein cholesterol
- simvastatin at therapeutically effective doses of 80 mg/day and higher is effective in lowering LDL-C in patients suffering with homozygous familial hypercholesterolemia.
- simvastatin may be administered as monotherapy to a patient suffering with HFH, or it may be administered in combination with other therapies which are suitable for the treatment of HFH.
- simvastatin may be co-adminstered with one or more additional drugs which are effective in lowering LDL cholesterol such as 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; and bile acid sequestrants.
- Agents such as aspirin and beta-blockers may also be co- administered with simvastatin.
- Simvastatin may also be administered in conjunction with therapies such as
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Homozygous familial hypercholesterolemia can be treated in patients suffering with this condition by administering a therapeutically effective amount of simvastatin. Dosages above 40 mg/day, and more particularly at or above 80 mg/day, were found to effectively reduce the LDL cholesterol levels in these patients.
Description
TITLE OF THE INVENTION
METHOD FOR TREATING HOMOZYGOUS FAMILIAL
HYPERCHOLESTEROLEMIA
RELATED APPLICATIONS
This application is a continuing application and claims priority to U.S. provisional application number 60/021 ,420, filed July 9, 1996, and to U.S. provisional application number 60/029,351, filed October 31 ,1996.
BACKGROUND OF THE INVENTION
Homozygous familial hypercholesterolemia (HFH) is a rare disorder characterized by the presence of two abnormal low density lipoprotein (LDL) receptor genes which results in the patient having dysfunctional LDL receptors. This results in severe hypercholesterolemia, particularly extreme elevations in LDL levels, and rapid development of coronary atherosclerosis and coronary heart disease in those who suffer with HFH. Most patients develop coronary disease in adolescence and usually do not survive beyond their teen-age years.
HMG-CoA reductase inhibitors such as compactin, lovastatin, simvastatin, pravastatin, etc., are believed to work by upregulating LDL receptor activity and increasing LDL removal from the blood. Since FH homozygotes do not have functional LDL receptors, this class of drugs was generally believed to be ineffective in these patients. Previous experience with HMG-CoA reductase inhibitors in FH homozygote children bore this out. For example, in J. Thiery, et al., European Journal of Pediatrics, (1990) 149: 716-721 , it is noted that compactin, at dosages as high as 200 mg per day, and lovastatin caused only marginal lowering of LDL cholesterol levels in HFΗ patients and therefore were not considered to be useful therapies for this condition.
The treatment options available to those suffering with HFH have been limited to liver transplantation or LDL aphaeresis therapy. LDL aphaeresis is a technique where plasma is removed from patients
and run over columns either with an antibody to apo B or reagents to precipitate LDL. It is usually performed once every two weeks in this population with about a 70% reduction in LDL cholesterol immediately after the procedure, with levels returning to baseline at one week post- treatment. Both treatment options are associated with considerable morbidity and are in limited supply.
More recently, a second-generation HMG-CoA reductase inhibitor, atorvastatin, has been shown to be useful for treating HFH.
Contrary to what was previously believed due to the nature of HFH and the mechanism of action understood to be associated with HMG-CoA reductase inhibitors as well as the available published studies in this field, it has been discovered that simvastatin (marketed in the U.S. under the trademark ZOCOR®) in doses above 40 mg per day can be used to treat patients suffering with HFH.
SUMMARY OF THE INVENTION
The main object of the instant invention is to provide a method for treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment. A person in need of such treatment is one who has homozygous familial hypercholesterolemia. Additional objects will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that simvastatin in daily dosages above 40 mg are useful for the treatment of HFH. Preferably, the daily dosage is at least 80 mg, and more preferably, at least 160 mg. The compound may be administered in a single daily dose, or divided doses, for example two, three or four times daily. Simvastatin may also be administered in a sustained release formulation, for example employing the formulation described in U.S. Patent No. 5,366,738. Sustained release and daily divided dose administration is preferred.
The following study results demonstrate the usefulness of simvastatin in the treatment of HFH.
I. Study Design
Design: double blinded, randomized, parallel, dose-escalation, controlled, 1 week study
Patients: 12 patients with well-characterized HFH Treatment: After a 4 week placebo diet run in period, the 12 patients were randomized to simvastatin (S) 80 mg/day (group 1 , n=8) or 40 mg/day (group 2, n=4). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day and treatment continued for an additional 9 weeks. Simvastatin was administered orally. The simvastatin treatment information is summarized in the table, below.
Period 1 (9 weeks) Period 2 (9 weeks)
Group 1 (n=8): 80 mg/day in 3 divided 160 mg/day in 3 divided doses doses Group 2 (n=4): 40 mg/day once a day 40 mg/day in 3 divided doses
Endpoint: Change in low density lipoprotein cholesterol
II. Study Results
The results of the study are as follows. For T-C, LDL-C and HDL-C, mean baseline and mean % change from baseline are shown; for TRIG, median baseline and median % change from baseline are shown:
GROUP 1 GROUP 2
(n=8) (n=4)
BL 80 160 BL 40 40
(mg/dl) mg/day mg/day (mg/dl) mg/day mg/day tid dosing tid dosing hs tid dosing
% change % change % change % change
T-C 627 -23 -29 562 -12 -13
LDL-C 570 -25 -31 519 -14 - 15
TRIG 136 -9 -15 72 7 - 1 1
HDL-C 32 12 6 28 1 1 17
BL = baseline
T-C = total cholesterol
LDL-C = low density lipoprotein cholesterol
TRIG = triglyceride level
HDL-C = high density lipoprotein cholesterol
All 12 patients completed the trial and there were no serious or unexpected adverse events. No patients sustained significant hepatic transaminase or creatine kinase elevations.
As can be seen from the above study results, simvastatin at therapeutically effective doses of 80 mg/day and higher is effective in lowering LDL-C in patients suffering with homozygous familial hypercholesterolemia.
As such, simvastatin may be administered as monotherapy to a patient suffering with HFH, or it may be administered in combination with other therapies which are suitable for the treatment of HFH. For example, simvastatin may be co-adminstered with one or more additional drugs which are effective in lowering LDL cholesterol such as 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 absoφtion inhibitors; and bile acid sequestrants. Agents such as aspirin and beta-blockers may also be co- administered with simvastatin. Simvastatin may also be administered in conjunction with therapies such as LDL aphaeresis.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated. Likewise, the specific pharmacological responses observed may vary depending upon the particular pharmaceutical carriers employed, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims
1. A method of treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment.
2. The method of claim 1 wherein the daily dosage of simvastatin is more than 40 mg.
3. The method of claim 2 wherein the daily dosage of simvastatin is at least 80 mg.
4. The method of claim 3 wherein the daily dosage of simvastatin is 80 mg.
5. The method of claim 2 wherein the daily dosage of simvastatin is at least 160 mg.
6. The method of claim 5 wherein the daily dosage of simvastatin is 160 mg.
7. The method of claim 1 wherein the simvastatin is administered in a single daily dose.
8. The method of claim 1 wherein the simvastatin is administered in divided daily doses.
9. The method of claim 1 wherein the simvastatin is administered in a controlled time-release formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU42289/97A AU4228997A (en) | 1996-07-09 | 1997-07-03 | Method for treating homozygous familial hypercholesterolemia |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2142096P | 1996-07-09 | 1996-07-09 | |
| US60/021,420 | 1996-07-09 | ||
| GB9617898.3 | 1996-08-28 | ||
| GBGB9617898.3A GB9617898D0 (en) | 1996-08-28 | 1996-08-28 | Method for treating homozygous familial hypercholesterolemia |
| US2935196P | 1996-10-31 | 1996-10-31 | |
| US60/029,351 | 1996-10-31 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998001100A2 true WO1998001100A2 (en) | 1998-01-15 |
| WO1998001100A3 WO1998001100A3 (en) | 1998-02-12 |
Family
ID=27268450
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/012426 WO1998001116A1 (en) | 1996-07-09 | 1997-07-03 | Therapy for combined hyperlipidemia |
| PCT/US1997/011792 WO1998001100A2 (en) | 1996-07-09 | 1997-07-03 | Method for treating homozygous familial hypercholesterolemia |
| PCT/US1997/010867 WO1998001119A2 (en) | 1996-07-09 | 1997-07-03 | Pharmaceutical compositions comprising simvastatin |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/012426 WO1998001116A1 (en) | 1996-07-09 | 1997-07-03 | Therapy for combined hyperlipidemia |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/010867 WO1998001119A2 (en) | 1996-07-09 | 1997-07-03 | Pharmaceutical compositions comprising simvastatin |
Country Status (2)
| Country | Link |
|---|---|
| AU (3) | AU3667297A (en) |
| WO (3) | WO1998001116A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000018395A1 (en) * | 1998-09-30 | 2000-04-06 | Warner-Lambert Company | Method for preventing or delaying catheter-based revascularization |
| WO2003055991A1 (en) * | 2001-12-21 | 2003-07-10 | Rigshospitalet | Igamete recruitment and developmental competence in mammals by inhibiting the de novo sterol biosynthesis and/or promoting sterol efflux |
| US6627757B2 (en) | 2001-03-28 | 2003-09-30 | Schering Corporation | Enantioselective synthesis of azetidinone intermediate compounds |
| US9056915B2 (en) | 2007-08-23 | 2015-06-16 | Amgen Inc. | Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9) |
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| 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 |
| US6982251B2 (en) | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| US7071181B2 (en) | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| IL156422A0 (en) | 2001-01-26 | 2004-01-04 | Schering Corp | The use of substituted azetidinone compounds for the treatment of sitosterolemia |
| CA2563051A1 (en) | 2001-01-26 | 2002-08-01 | Schering Corporation | Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| ATE345793T1 (en) | 2001-09-21 | 2006-12-15 | Schering Corp | TREATMENT OF XANTHOMA USING AZETIDINONE DERIVATIVES AS 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 |
| AR040588A1 (en) | 2002-07-26 | 2005-04-13 | Schering Corp | PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE |
| WO2004043456A1 (en) | 2002-11-06 | 2004-05-27 | Schering Corporation | Cholesterol absorption inhibitors for the treatment of demyelination |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| ES2318274T3 (en) | 2003-03-07 | 2009-05-01 | Schering Corporation | AZETIDINONA SUBSTITUTED COMPOUNDS, FORMULATIONS AND USE OF THE SAME FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA. |
| JP2006519869A (en) | 2003-03-07 | 2006-08-31 | シェーリング コーポレイション | Substituted azetidinone compounds, processes for preparing substituted azetidinone compounds, their formulations and uses |
| ATE406364T1 (en) | 2003-03-07 | 2008-09-15 | Schering Corp | SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4806564A (en) * | 1987-05-26 | 1989-02-21 | Merck & Co., Inc. | Antihypercholesterolemic beta-lactones |
| 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 |
-
1997
- 1997-07-03 WO PCT/US1997/012426 patent/WO1998001116A1/en active Application Filing
- 1997-07-03 AU AU36672/97A patent/AU3667297A/en not_active Abandoned
- 1997-07-03 WO PCT/US1997/011792 patent/WO1998001100A2/en active Application Filing
- 1997-07-03 AU AU42289/97A patent/AU4228997A/en not_active Abandoned
- 1997-07-03 WO PCT/US1997/010867 patent/WO1998001119A2/en active Application Filing
- 1997-07-03 AU AU43261/97A patent/AU4326197A/en not_active Abandoned
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000018395A1 (en) * | 1998-09-30 | 2000-04-06 | Warner-Lambert Company | Method for preventing or delaying catheter-based revascularization |
| EA007427B1 (en) * | 1998-09-30 | 2006-10-27 | Варнер Ламберт Компани | Method for preventing or delaying catheter-based revascularization |
| AP1708A (en) * | 1998-09-30 | 2007-01-10 | Warner Lambert Co | Method for preventing or delaying catheter-based revascularization. |
| US6627757B2 (en) | 2001-03-28 | 2003-09-30 | Schering Corporation | Enantioselective synthesis of azetidinone intermediate compounds |
| WO2003055991A1 (en) * | 2001-12-21 | 2003-07-10 | Rigshospitalet | Igamete recruitment and developmental competence in mammals by inhibiting the de novo sterol biosynthesis and/or promoting sterol efflux |
| US9056915B2 (en) | 2007-08-23 | 2015-06-16 | Amgen Inc. | Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9) |
| US9920134B2 (en) | 2007-08-23 | 2018-03-20 | Amgen Inc. | Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9) |
Also Published As
| Publication number | Publication date |
|---|---|
| AU4228997A (en) | 1998-02-02 |
| AU4326197A (en) | 1998-02-02 |
| WO1998001100A3 (en) | 1998-02-12 |
| AU3667297A (en) | 1998-02-02 |
| WO1998001116A1 (en) | 1998-01-15 |
| WO1998001119A2 (en) | 1998-01-15 |
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