WO1996008239A1 - Use of 5-alpha-reductase inhibitors to increase hdl cholesterol levels - Google Patents

Use of 5-alpha-reductase inhibitors to increase hdl cholesterol levels Download PDF

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Publication number
WO1996008239A1
WO1996008239A1 PCT/US1995/007215 US9507215W WO9608239A1 WO 1996008239 A1 WO1996008239 A1 WO 1996008239A1 US 9507215 W US9507215 W US 9507215W WO 9608239 A1 WO9608239 A1 WO 9608239A1
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Prior art keywords
inhibitor
reductase inhibitor
reductase
administration
hmg
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PCT/US1995/007215
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English (en)
French (fr)
Inventor
Jonathan A. Tobert
Keith D. Kaufman
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Merck & Co., Inc.
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Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU27684/95A priority Critical patent/AU2768495A/en
Publication of WO1996008239A1 publication Critical patent/WO1996008239A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • Cholesterol is a major building block of all plasma membranes and a key compound for the synthesis of steroid hormones and bile salts. Cholesterol and triglycerides are lipophilic and cannot dissolve in water and thus cannot travel through the bloodstream in their unaltered forms. They are made water-soluble by combining with proteins produced by the liver and intestine called apolipoproteins and the complexes thus formed are called lipoproteins, which vary in size, weight and density. Two of the major classes are called low-density lipoproteins (LDLs) and high density lipoproteins (HDLs). LDL contains 60 to 70 percent of serum cholesterol and is believed to pick up cholesterol and deposit it in body cells, including smooth muscle cells in arteries.
  • LDLs low-density lipoproteins
  • HDLs high density lipoproteins
  • HDL which contains 20 to 30 percent of total serum cholesterol
  • VLDL very low density lipoprotein
  • MEVACOR® lovastatin
  • ZOCOR® simvastatin
  • PRAVACHOL® pravastatin
  • LESCOL® fluvastatin
  • lipid-lowering drugs including niacin (nicotinic acid), fibrates such as gemfibrozil, and inhibitors of HMG-CoA reductase, such as lovastatin and simvastatin.
  • niacin nicotinic acid
  • fibrates such as gemfibrozil
  • HMG-CoA reductase such as lovastatin and simvastatin.
  • HMG-CoA reductase such as lovastatin and simvastatin.
  • the fibrates have the side effects of gastrointestinal disturbances and an increased risk of gallstones.
  • HMG-CoA reductase inhibitors are relatively safe and well- tolerated, their effect on HDL-cholesterol is small, usually about less than 10%, even at maximum dose.
  • the compounds employed in the present invention are 5cc- reductase inhibitors.
  • Finasteride PROSCAR®
  • PROSCAR® is a commercially available 5 -reductase inhibitor
  • BPH benign prostatic hype ⁇ lasia
  • Inhibition of 5 -reductase is extremely well-tolerated, probably because the only known function of the enzyme in adults is to support certain male secondary sexual characteristics, including prostate growth.
  • Males who are homozygous for 5 ⁇ -reductase deficiency have small prostates and do not develop BPH.
  • Women who are homozygous for 5 -reductase deficiency are phenotypically normal, indicating that the enzyme serves no general biological pu ⁇ ose.
  • Finasteride the first member of this class to be available for prescription, is a very well- tolerated drug. It is well known that the concentration of HDL cholesterol is lower in men than in women.
  • 5 -reductase inhibitors increases serum HDL cholesterol levels.
  • lipid lowering agents such as HMG-CoA reductase inhibitors, squalene synthase inhibitors, HMG-CoA synthase inhibitors, bile acid sequestrants, niacin, probucol, and the fibric acids to reduce the risk of coronary artery disease mortality and morbidity.
  • two or more 5 -reductase inhibitors may be used in combination to increase serum HDL cholesterol levels.
  • This invention relates to the use of 5 ⁇ -reductase inhibitors to increase serum (or plasma) HDL cholesterol levels either alone or in combination with other lipid-altering agents.
  • 5 -reductase inhibitor as used herein is intended to include compounds which are active as inhibitors of either or both of the isozymes of 5 ⁇ -reductase, such as, e.g., inhibitors of 5 ⁇ - reductase type 1, such as, e.g., 4,7 ⁇ -dimethyl-4-aza-5 -cholestan-3-one (also known as MK-386; as disclosed in WO 93/23420 to Merck & Co., Inc.), inhibitors of 5 ⁇ -reductase type 2, such as, e.g., finasteride, epristeride (also known as SKF-105657, SmithKline Beecham), ONO- 3805 (Ono Pharmaceutical Co., Ltd.), FK-143 (Fujisawa), KF- 18678 to Kyowa Hakko-Koygo and TZP-4238 (Teikokuzoki), and those which are active as dual inhibitors of both isozymes type 1 and
  • reductase type 1 with an inhibitor of 5 ⁇ -reductase type 2, such as, e.g., the use of a combination of finasteride with MK-386.
  • an inhibitor of 5 ⁇ -reductase type 2 such as, e.g., the use of a combination of finasteride with MK-386.
  • Many compounds which are 5 ⁇ -reductase inhibitors have been described in the art; compounds which are 5 ⁇ -reductase inhibitors can also be determined by the 5cc-reductase assay, further described below.
  • Examples of compounds which are 5 -reductase inhibitors include, but are not limited to, those described in the following patents and publications: U.S. Patent No's: 5,017,568; 5,061 ,803; 5,061 ,801 ; 5,061 ,802; 5,026,882; 4,377,584; 4,760,071 ; 4,845,104; 4,859,681 ; 5,049,562; 5,120,742; 5,138,063; 5,302,528; 5,302,528; and
  • Especially preferred 5 ⁇ -reductase inhibitors are the following:
  • the 5 ⁇ -reductase inhibitors of the present invention may also be beneficially administered as a combination of 5 ⁇ -reductase inhibitors.
  • administration refers to both concurrent and sequential administration of the active agents.
  • a combination of a Type 1 and a Type 2 5 ⁇ -reductase inhibitor is especially preferred.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
  • pharmacologically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any particularly specified number of carbon atoms.
  • alkyl or its prefix root appears in a name of a substituent (e.g., aralkoxyaryloxy) it shall be inte ⁇ reted as including those limitations given above for "alkyl", unless otherwise indicated.
  • the compounds of the present invention can be admin ⁇ istered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Like ⁇ wise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an agent to increase HDL cholesterol levels.
  • the dosage regimen utilizing the compounds of the present invention 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 thereof employed.
  • An ordinarily skilled physician or veter ⁇ inarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.05 to 1000 mg/day orally.
  • the compositions are preferably provided in the form of tablets containing 0.2, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 and 50.0 mg of active ingredient.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
  • Other preferred topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of active ingredient would range from 0.1 % to 15%, w/w or w/v.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers 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.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy- ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of this invention may also be administered in combination with other cholesterol lowering agents such as those which inhibit an enzymatic pathway in the biosynthesis of cholesterol. Such administration includes concurrent as well as sequential administration. Examples of such agents would include but are not limited to HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthase inhibition.
  • HMG-CoA reductase inhibitors are lovastatin and related compounds as disclosed in U.S. Patent No. 4,231 ,938 simvastatin and related compounds such as disclosed in U.S. Patent No.
  • HMG-CoA synthase inhibitors are: 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
  • squalene synthetase inhibitors including the triacids thereof, triesters thereof and tripotassium and trisodium salts thereof as well as other squalene synthetase inhibitors disclosed in pending U.S. Patent No. 4,871 ,721 and 4,924,024 and in Biller et al, J. Med.Chem., 1988, Vol. 31, No. 10, pp. 1869 to 1871.
  • other squalene synthetase inhibitors suitable for use herein include the te ⁇ enoid pyrophosphates disclosed by P. Ortiz de Montellano et al., J. Med.
  • the benzodiazepine squalene synthase inhibitors described in EP O 567 026 to Takeda Chemical Industries the quinuclidinyl squalene synthase inhibitors described in PCT publications WO 94/03451 , WO 93/09115, WO 93/21 183, WO 93/21 184, WO 93/24486, and U.S. 5,135,935, may be employed in combination with the 5 ⁇ -reductase inhibitors 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 Application Serial No. 07/670,640 filed March 18, 1991.
  • Other cholesterol lowering agents include niacin, probucol, and the fibric acids, clofibrate and gemfibrozil.
  • the dose of HMG-CoA reductase inhibitor contemplated for use in the co-administration of the present invention are from about 1 to 200 mg per day, preferably given in single or divided doses. Most preferred are dosages from 5 to 80 mg per day.
  • the doses of HMG-CoA synthase inhibitor contemplated for use in the co-administration of the present invention are from about 20 to 200 mg, preferably given in single or divided doses.
  • the doses of squalene synthase inhibitor contemplated for use in the co-administration of the present invention are from about 2 to 2000 mg per day, preferably given in single or divided doses.
  • the doses of squalene epoxidase inhibitor contemplated for use in the co-administration of the present invention are from 2 to 200 mg per day, preferably given in single or divided doses.
  • Additional combinations are those containing 0.01 to 1000 mg of a 5oc-reducta.se inhibitor in combination with up to 1000 mg probucol, up to 2 g clofibrate, 0.5 to 8 g of niacin, 800 to 1500 mg gemfibrozil or fenofibrate, or 20 to 300 mg of an LDL receptor gene inducer.
  • the 5cc-reductase inhibitors of the present invention may also be co-administered with pharmaceutically acceptable nontoxic cationic polymers capable of binding beta acids in a non- resorbable form in the gastrointestinal tract.
  • pharmaceutically acceptable nontoxic cationic polymers capable of binding beta acids in a non- resorbable form in the gastrointestinal tract.
  • examples of such polymers include cholestyramine, colestipol, and poly[methyl-(3- trimethylaminopropyl)imino-trimethylene dihalide].
  • Lipids Study Design A 60-week, double-blind, radomized, placebo-controlled, multicenter study was conducted in which 137 healthy male subjects were assigned to begin the 2 week placebo run-in period at the Week -2 visit. The subjects were allocated to receive either finasteride 5 mg (PROSCAR®) or placebo for 24 weeks at the Week 1 visit. At the end of the active treatment period (Week 24) subjects discontinued the assigned medication. Thirty-six weeks after stopping the medication (Week 60), subjects were seen in the clinic for the final visit.
  • finasteride 5 mg PROSCAR®
  • Week 1 visit At the end of the active treatment period (Week 24) subjects discontinued the assigned medication. Thirty-six weeks after stopping the medication (Week 60), subjects were seen in the clinic for the final visit.
  • Fasting lipid profile (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, VLDL cholesterol, Lp(a), apoAI, All, B) was obtained at Weeks 1, 12, 24 and 60. The subject must have fasted for a minimum of 12 hours. The serum was frozen at -20°C for shipment to a central reference laboratory for analysis.
  • Tables 1 and 2 contain the results of the percent change at Week 12 or Week 24, respectively, from Week 1 (baseline) for total cholesterol (tot. chol), HDL cholesterol (hdl), LDL cholesterol (ldl), and triglycerides (trig).
  • variable group N mean std med p-value p-value within between
  • PROSCAR ® 56 4.5 14.7 2.1 0.019 0.081 ldl
  • PROSCAR® 56 0.6 19.2 1.6 0.878 0.681
  • variable group N mean std med p-value p-value within between
  • PLACEBO 48 0.4 12.1 0.2 0.755
  • PROSCAR ® 53 9.1 14.5 6.8 0.000 0.022 ldl
  • Tables 3 and 4 contain the results at Week 12 and Week 24, respectively, of change from Week 1 in mg/dl for each variable, i.e., the change in each measurement unit for each of the above variables.
  • variable group N mean std med p-value p-value within between
  • PLACEBO 51 2.0 18.9 5.0 0.377
  • PROSCAR® 56 1.4 23.8 1.0 0.580 0.882 hdl
  • PROSCAR® 56 1.5 7.3 1.0 0.043 0.134 ldl
  • PLACEBO 51 0.5 15.6 2.0 0.686
  • variable group N mean std med p-value p-value within between
  • PROSCAR ® 53 1.6 18.4 1.0 0.590 0.090
  • Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl- sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • a crude nuclear pellet was prepared by centrifugation of the homogenate at 1 ,500 x g for 15 min. The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%.
  • the enzyme suspension was frozen in aliquots at -80°C. The prostatic and scalp reductases were stable for at least 4 months when stored under these conditions. 5 -reductase assay
  • the reaction mixture for the type 1 5 ⁇ -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H] -testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min. the reaction was quenched by extraction with 250 ⁇ l of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 ⁇ m in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC (10 cm Whatman partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min.; androstanediol, 7.6-8.0 min.; T, 9.1-9.7 min.).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A 120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM.
  • a compound referred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • a compound referred to herein as a 5 ⁇ -reductase type 1 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase type 1 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • a compound referred to herein as a dual 5 -reductase type 1 and 2 inhibitor is a compound that shows inhibition of both the type 1 and type 2 isozymes, having an IC50 value of about or under 100 nM for each isozyme.
  • an oral composition of a compound of this invention 5 mg finasteride and 40 mg simvastatin are formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

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PCT/US1995/007215 1994-09-13 1995-06-06 Use of 5-alpha-reductase inhibitors to increase hdl cholesterol levels WO1996008239A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077072A3 (en) * 2000-04-11 2002-07-18 Atherogenics Inc Compounds and methods to increase plasma hdl cholesterol levels and improve hdl functionality
US6630164B2 (en) * 2000-05-09 2003-10-07 Kenneth Weisman Dutasteride to prevent and treat atherosclerosis
US7169768B1 (en) * 1997-03-18 2007-01-30 Weisman Kenneth M Method of decreasing atherosclerosis and its complications

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000147A1 (en) * 1993-06-28 1995-01-05 Merck & Co., Inc. 4-AZA-PREGNANE 5α-REDUCTASE ISOZYME 1 INHIBITORS

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000147A1 (en) * 1993-06-28 1995-01-05 Merck & Co., Inc. 4-AZA-PREGNANE 5α-REDUCTASE ISOZYME 1 INHIBITORS

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Androgen Osaterone Acetate (TZP-4238)", PHARMACOMETRICS, vol. 47, no. 3 *
"Effects of finasteride (MK-906), a 5-alpha reductase inhibitor, on circulating androgens in male volunteers", J.CLIN.ENDOCRINOL.METAB., vol. 70, no. 4, pages 1136 - 41 *
"HDL response to 5-alpha dihydrotestosterone and testosterone in Macaca Fascicularis: a hormone-responsive primate model for the study of atherosclerosis", METABOLISM, vol. 39, no. 9, pages 919 - 24 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7169768B1 (en) * 1997-03-18 2007-01-30 Weisman Kenneth M Method of decreasing atherosclerosis and its complications
WO2001077072A3 (en) * 2000-04-11 2002-07-18 Atherogenics Inc Compounds and methods to increase plasma hdl cholesterol levels and improve hdl functionality
US6881860B2 (en) 2000-04-11 2005-04-19 Atherogenics, Inc. Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality
US7183317B2 (en) 2000-04-11 2007-02-27 Atherogenics, Inc. Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality
US6630164B2 (en) * 2000-05-09 2003-10-07 Kenneth Weisman Dutasteride to prevent and treat atherosclerosis

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