Patent Publication Number: US-2004058908-A1

Title: Combinations for cardiovascular indications

Description:
[0001] This application claims priority of U.S. provisional application Ser. No. 60/113,955 filed Dec. 23, 1998. 
    
    
     
       BACKGROUND OF THE INVENTION  
       [0002] 1. Field of the Invention  
       [0003] The present invention relates to methods of treating cardiovascular diseases, and specifically relates to combinations of compounds, compositions, and methods for their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as are associated with atherosclerosis, hypercholesterolemia, and other factors in coronary artery disease in mammals including hypertension. More particularly, the invention relates to ileal bile acid transporter (IBAT) inhibitors, cholesteryl ester transfer protein (CETP) activity inhibitors, fibric acid derivatives (fibrates), nicotinic acid derivatives, microsomal triglyceride transfer protein (MTP) inhibitors, cholesterol absorption antagonists, stanols, phytosterols, or antihypertensive agents.  
       [0004] 2. Description of Related Art  
       [0005] It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye,  Atherosclerosis,  121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.  
       [0006] Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above about 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases or risk factors, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios.  
       [0007] Interfering with the recirculation of bile acids from the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,”  Biochimica et Biophysica Acta,  1210, 255-287 (1994) discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.  
       [0008] Transient pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans with an inherited lack of IBAT activity, as reported by Heubi, J. E., et al. See “Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport”,  Gastroenterology,  83, 804-11 (1982).  
       [0009] In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al., “Intestinal Bile Acid Absorption”  The Journal of Biological Chemistry,  268 (24), 18035-46 (1993).  
       [0010] In several individual patent applications, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents. The individual Hoechst patent applications which disclose such bile acid transport inhibiting compounds are each separately listed below.  
       [0011] R1. Canadian Patent Application No. 2,025,294.  
       [0012] R2. Canadian Patent Application No. 2,078,588.  
       [0013] R3. Canadian Patent Application No. 2,085,782.  
       [0014] R4. Canadian Patent Application No. 2,085,830.  
       [0015] R5. EP Application No. 0 379 161.  
       [0016] R6. EP Application No. 0 549 967.  
       [0017] R7. EP Application No. 0 559 064.  
       [0018] R8. EP Application No. 0 563 731.  
       [0019] Selected benzothiepines are disclosed in world patent application number WO 93/321146 for numerous uses including fatty acid metabolism and ccronary vascular diseases.  
       [0020] Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed in application No. EP 508425. A French patent application, FR 2661676 discloses additional benzothiepines for use as hypolipaemic and hypocholesterolaemic agents. Furthermore, patent application no. WO 92/18462 lists other benzothiepines for use as hypolipaemic and hypocholesterolaemic agents. U.S. Pat. No. 5,994,391 (Lee et al.) Each of the benzothiepine hypolipaemic and hypocholesterolaemic agents described in these individual patent applications is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclobenzothiepine ring.  
       [0021] Further benzothiepines useful for the treatment of hypercholesterolemia arid hyperlipidemia are disclosed in patent application no. PCT/US95/10863. More benzothiepines useful for the prophylaxis and treatment of hypercholesterolemia and hyperlipidemia as well as pharmaceutical compositions of such benzothiepines are described in PCT/US97/04076. Still further benzothiepines and compositions thereof useful for the prophylaxis and treatment of hypercholesterolemia and hyperlipidemia are described in U.S. application Ser. No. 08/816,065.  
       [0022] In vitro bile acid transport inhibition is disclosed to correlate with hypolipidemic activity in The Wellcome Foundation Limited disclosure of the Patent Application No. WO 93/16055 for “Hypolipidemic Benzothiazepine Compounds.” That publication describes a number of hypolipidemic benzothiazepine compounds. Additional hypolipidemic benzothiazepine compounds (particularly 2,3,4,5-tetrahydrobenzo-1-thi-4-azepine compounds) are disclosed in Patent Application No. WO 96/05188. A particularly useful benzothiazepine disclosed in WO 96/05188 is the compound of formula B-2. Further hypolipidemic benzothiazepine compounds are described in Patent Application No. WO 96/16051.  
                 
 
       (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1-4-benzothiazepine 1,1-dioxide  
       [0023] Other benzothiazepine compounds useful for control of cholesterol are 2,3,4,5-tetrahydrobenzo-1-thi-5-azepine IBAT inhibitor compounds described in PCT Patent Application No. WO 99/35135. Included in that description is the compound of formula B-7.  
                 
 
       [0024] Further IBAT inhibitor compounds include a class of naphthalene IBAT inhibitor compounds, described by T. Ichihashi et al. in  J. Pharmacol. Exp. Ther.,  284(1), 43-50 (1998). In this class, S-8921 (methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate) is particularly useful. The structure of S-8921 is shown in formula B-20. Further naphthalene compounds or lignin derivatives useful for the treatment or prophylaxis of hyperlipidemia or atherosclerosis are described in PCT Patent Application No. WO 94/24087.  
                 
 
       [0025] Another class of lipid-lowering drug is an anti-obesity drug. An example of an antiobesity drug is orlistat. Orlistat is described in European Patent No. EP 0 129 748.  
       [0026] Inhibition of cholesteryl ester transfer protein (CETP) has been shown to effectively modify plasma HDL/LDL ratios, and is expected to check the progress and/or formation of certain cardiovascular diseases. CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall,  J. Lipid Res.,  34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile. Evidence of this effect is described in McCarthy,  Medicinal Res. Revs.,  13, 139-59 (1993). Further evidence of this effect is described in Sitori,  Pharmac. Ther.,  67, 443-47 (1995)). This phenomenon was first demonstrated by Swenson et al., ( J. Biol. Chem.,  264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibits CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. ( Biochim. Biophys. Acta,  795, 743-480 (1984)) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, herein incorporated by reference, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. ( Biochim. Biophys. Acta  1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. ( J. Peptide Res.,  51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depspeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in  Bioorg. Med. Chem. Lett.,  8, 1277-80 (1998).  
       [0027] There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. ( J. Am. Chem. Soc.,  188, 7863-63 (1996)) describe cyclopropane-containing CETP inhibitors. Further cyclopropane-containing CETP inhibitors are described by Kuo et al. ( J. Am. Chem. Soc.,  117, 10629-34 (1995)). Pietzonka et al. ( Bioorg. Med. Chem. Lett.,  6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. ( Bioorg. Med. Chem. Lett.,  5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Lee et al. ( J. Antibiotics,  49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. ( Lipids,  25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit ( J. Lipid Res.,  35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. ( Biochem. Biophys. Res. Comm.,  223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors ( Bioorg. Med. Chem. Lett.,  6, 919-22 (1996)). Bisgaier et al. ( Lipids,  29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Additional triazole CETP inhibitors are described in U.S. patent application Ser. No. 09/153,360, herein incorporated by reference. Sikorski et al. disclosed further novel CETP inhibitors in PCT Patent Application No. WO 9914204.  
       [0028] Substituted 2-mercaptoaniline amide compounds can be used as CETP inhibitors and such therapeutic compounds are described by H. Shinkai et al. in PCT Patent Application No. WO 98/35937.  
       [0029] Some substituted heteroalkylamine compounds are known as CETP inhibitors. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-substituted pyridines as cholesterol ester transfer protein inhibitors useful as cardiovascular agents. One substituent at C 3  of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to be β3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and atherosclerotic diseases. In European Patent Application No. 818448 (herein incorporated by reference), Schmidt et al. describe tetrahydroquinoline derivatives as cholesterol ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesterol ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesterol ester transfer protein inhibitors. In PCT Patent Application No. WO 9839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors.  
       [0030] Polycyclic compounds that are useful as CETP inhibitors are also disclosed by A. Oomura et al. in Japanese Patent No. 10287662. For example, therapeutic compounds having the structures C-1 and C-8 were prepared by culturing Penicillium spp.  
       [0031] Cycloalkylpyridines useful as CETP inhibitors are disclosed by Schmidt et al. in European Patent No. EP 818448. For example, the therapeutic compound having the structure C-9 is disclosed as being particularly effective as a CETP inhibitor.  
       [0032] Substituted tetrahydronaphthalene compounds useful as CETP inhibitors are described in PCT Patent Application No. WO 9914174. Specifically described in that disclosure as a useful CETP inhibitor is (8S)-3-cyclopentyl-1-(4-fluorophenyl)-2-[(S)-fluoro(4-trifluoromethylphenyl)methyl]-8-hydroxy-6-spirocclobutyl-5,6,7,8-tetrahydronaphthalene.  
       [0033] Some 4--heteroaryl-tetrahydroquinolines useful as CETP inhibitors are described in PCT Patent Application No. WO 9914215. For example, that disclosure describes 3-(4-trifluoromethylbenzoyl)-5,6,7,8-tetrahydroquinolin-5-one as a useful CETP inhibitor.  
       [0034] In another approach to the reduction of total cholesterol, use is made of the understanding that HMG CoA reductase catalyzes the rate-limiting step in the biosynthesis of cholesterol ( The Pharmacological Basis of Therapeutics,  9th ed., J. G. Hardman and L. E. Limberd, ed., McGraw-Hill, Inc., New York, pp. 884-888 (1996), herein incorporated by reference). HMG CoA reductase inhibitors (including the class of therapeutics commonly called “statins”) reduce blood serum levels of LDL cholesterol by competitive inhibition of this biosynthetic step (M. S. Brown, et al., J. Biol. Chem, 253, 1121-28 (1978), herein incorporated by reference). Several statins have been developed or commercialized throughout the world. Mevastatin was among the first of the statins to be developed and it is described in U.S. Pat. No. 3,983,140 (herein incorporated by reference). Lovastatin, another important HMG CoA reductase inhibitor, is described in U.S. Pat. No. 4,231,938 (herein incorporated by reference). Simvastatin is described in U.S. Pat. No. 4,444,784 (herein incorporated by reference). Each of these HMG CoA reductase inhibitors contains a six-membered lactone function which apparently mimics the structure of HMG CoA in competition for the reductase. The HMG CoA reductase inhibitor class of cholesterol-lowering drugs is further exemplified by a group of drugs which contain 2,4-dihydroxyheptanoic acid functionalities rather than the lactone. One member of this group is pravastatin, described in U.S. Pat. No. 4,346,227 (herein incorporated by reference). Another HMG CoA reductase inhibitor which contains a 2,4-dihydroxyheptanoic acid group is fluvastatin, described in U.S. Pat. No. 5,354,772 (herein incorporated by reference). Warnings of side effects from use of HMG CoA reductase inhibitors include liver dysfunction, skeletal muscle myopathy, rhabdomyolysis, and acute renal failure. Some of these effects are exacerbated when HMG CoA reductase inhibitors are combined with fibrates or nicotinic acid.  
       [0035] Fibric acid derivatives comprise another class of drugs which have effects on lipoprotein levels. Among the first of these to be developed was clofibrate, disclosed in U.S. Pat. No. 3,262,850. Clofibrate is the ethyl ester of p-chlorophenoxyisobutyric acid. A widely used drug in this class is gemfibrozil, disclosed in U.S. Pat. No. 3,674,836. Gemfibrozil frequently is used to decrease triglyceride levels or increase HDL cholesterol concentrations ( The Pharmacological Basis of Therapeutics,  p. 893). Fenofibrate (U.S. Pat. No. 4,058,552) has an effect similar to that of gemfibrozil, out additionally decreases LDL levels. Ciprofibrate (U.S. Pat. No. 3,948,973) has similar effects to that of fenofibrate. Another drug in this class is bezafibrate (U.S. Pat. No. 3,781,328). Warnings of side effects from use of fibric acid derivatives include gall bladder disease (cholelithiasis), rhabdomyolysis, and acute renal failure. Some of these effects are exacerbated when fibrates are combined with HmG CoA reductase inhibitors.  
       [0036] Probucol is a powerful antioxidant which has shown the ability to lower serum cholesterol levels and cause regression of xanthomas in patients having homozygous familial hypercholesterolemia (A. Yamamoto, et al., Am. J. Cardiol., 57, 29H-35H (1986)). However, treatment with probucol alone sometimes shows erratic control of LDL and frequent lowering of HDL ( The Pharmacological Basis of Therapeutics , p. 891). Probucol is contraindicated for patients with progressive myocardial damage and/or ventricular arrhythmias.  
       [0037] A class of materials which operates by another mechanism to lower LDL cholesterol comprises bile acid sequestering agents. Such agents are typically anion exchange polymers administered orally to a patient. As the agent passes through the gut, anions of bile acids are sequestered by the agent and excreted. Such sequestering has been speculated to prevent reabsorption by the gut, for example the ileum, thereby preventing conversion of the bile acids into cholesterol. One such bile acid sequestering agent is cholestyramine, a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids. It is believed that cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation. This effect is described by Reihnér et al., in “Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-COA reductase activity and low density lipoprotein receptor expression in gallstone patients”, Journal of Lipid Research, 31, 2219-2226 (1990). Further description of this effect is found in Suckling et al. in “Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment”,  Atherosclerosis,  89, 183-90 (1991). This results in an increase in liver bile acid synthesis because of the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.  
       [0038] Another bile acid sequestering agent is colestipol, a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane. Colestipol is described in U.S. Pat. No. 3,692,895. A frequent side effect of colestipol and of cholestyramine is gastric distress.  
       [0039] Additional bile acid sequestering agents are described in U.S. Pat. No. 5,703,188, assigned to Geltex Pharmaceuticals Inc. For example, one such bile acid sequestering agent is 3-methacrylamidopropyltrimethylammonium chloride copolymerized with ethylene glycol dimethacrylate to yield a copolymer.  
       [0040] Yet another class materials proposed as bile acid sequestering agents comprises particles comprising amphiphilic copolymers having a crosslinked shell domain and an interior core domain (Patent application no. PCT/US 97/11610). Structures and preparation of such crosslinked amphiphilic copolymers are described in PCT/US97/11345. Such particles have been given the common name of “knedels” (K. B. Thurmond et al., J. Am. Chem. Soc., 118 (30), 7239-40 (1996)).  
       [0041] Nicotinic acid (niacin) is a B-complex vitamin reported as early as 1955 to act as a hypolipidemic agent (R. Altschl, et al., Arch. Biochem. Biophys., 54, 558-9 (1955)). It is sometimes used to raise low HDL levels and lower VLDL and LDL levels. Useful commercial formulations of nicotinic acid include Niacor, Niaspan, Nicobid, Nicolar, Slo-Niacin. Nicotinic acid is contraindicated for patients having hepatic dysfunction, active peptic ulcer, or arterial bleeding. Another compound in this class useful for cardiovascular indications is niceritrol (T. Kazumi et al., Curr. Ther. Res., 55, 546-51). J. Sasaki et al. (Int. J. Clin. Pharm. Ther., 33 (7), 420-26 (1995)) describes a reduction in cholesterol ester transfer activity by niceritrol monotherapy. Acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide, U.S. Pat. No. 4,002,750) is structurally similar to nicotinic acid and has antihyperlipidemic activity.  
       [0042] A study by Wetterau et al. ( Science,  282, 751-54 (1998)) describes a number of alkylpiperidine compounds, isoindole compounds, and fluorene compounds useful for inhibiting microsomal triglyceride transfer protein (MTP inhibitors). Rodents and Watanabe-heritable hyperlipidemic rabbits treated with these compounds show decreased production of lipoprotein particles.  
       [0043] Cholesterol absorption antagonists may also be useful for the treatment of prophylaxis of cardiovascular diseases such as hypercholesterolemia or atherosclerosis. For example, azetidinones such as SCH 58235 ([3R-[3α(S*),4β]]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone) (formula A-1), described in  J. Med. Chem.,  41(6), 973-980 (1998), are useful cholesterol absorption antagonists. SCH 58235 is further described by Van Heek et al. in  J. Pharmacol. Exp. Ther.,  283(1), 157-163 (1997). Further azetidinone compounds useful for treatment or prophylaxis of cardiovascular disease are described in U.S. Pat. No. 5,767,115.  
                 
 
       [3R-[3a(S*),4b]]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone  
       [0044] Phytosterols, and especially stanols have been shown to effectively inhibit cholesterol absorption from the gastrointestinal tract, and to negatively affect cholesterol synthesis. Phytosterols are expected to slow or inhibit the progress and formation of certain cardiovascular conditions, including hyperlipidemic conditions such as hypercholesterolemia and atherosclerosis. Stanols are 5α saturated derivatives of phytosterols. (Straub, U.S. Pat. No. 5,244,887). It has been suggested that phytosterols lower blood cholesterol levels by reducing the absorption of cholesterol from the intestine (Ling and Jones, “Minireview Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects,”  Life Sciences,  57 (3), 195-206 (1995)).  
       [0045] Sitostanol, clionastanol, 22,23-dihydrobrassica-stanol, campestanol, and mixtures thereof contained in food additives intended to reduce cholesterol absorption from foods and beverages containing cholesterol are described by Straub in U.S. Pat. No. 5,244,887.  
       [0046] A beta-sitostanol fatty acid ester or fatty acid ester mixture which lowers cholesterol in serum is described by Miettinen et al. in U.S. Pat. No. 5,502,045.  
       [0047] A stanol composition containing in sitostanol and campestanol which effectively lowers serum cholesterol levels when incorporated into edibles is described by Wester et al. in WO 9806405.  
       [0048] A therapeutic composition of one or more oxysterols and a suitable carrier to inhibit cholesterol absorption from the diet is described by Haines in U.S. Pat. No. 5,929,062.  
       [0049] Cardiovascular disease is also caused or aggravated by hypertension. Hypertension is defined as persistently high blood pressure. Generally, adults are classified as being hypertensive when systolic blood pressure is persistently above 140 mmHg or when diastolic blood pressure is above 90 mmHg. Long-term risks for cardiovascular mortality increase in a direct relationship with persistent blood pressure (E. Braunwald,  Heart Disease,  5th ed., W.B. Saunders &amp; Co., Philadelphia, 1997, pp. 807-823). Various mechanisms have been advantageously exploited to control hypertension. For example, useful antihypertensive agents can include, without limitation, an andrenergic blocker, a mixed alpha/beta andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, an andrenergic stimulant, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker, a diuretic, or a vasodilator. A particularly useful antihypertensive agent is eplerenone (see, for example, U.S. Pat. No. 4,559,332). Eplerenone lowers blood pressure by functioning as a diuretic. Eplerenone was formerly called epoxymexrenone.  
       [0050] Some combination therapies for the treatment of cardiovascular disease have been described in the literature. Combinations of IBAT inhibitors with HMG CoA reductase inhibitors useful for the treatment of cardiovascular disease are disclosed in U.S. patent application Ser. No. 09/037,308 and in PCT Patent Application No. 98/40375.  
       [0051] A combination therapy of fluvastatin and niceritrol is described by J. Sasaki et al. (Id.). Those researchers conclude that the combination of fluvastatin with niceritrol “at a dose of 750 mg/day dose does not appear to augment or attenuate beneficial effects of fluvastatin.” 
       [0052] L. Cashin-Hemphill et al. (J. Am. Med. Assoc., 264 (23), 3013-17 (1990)) describe beneficial effects of a combination therapy of colestipol and niacin on coronary atherosclerosis. The described effects include nonprogression and regression in native coronary artery lesions.  
       [0053] A combination therapy of acipimox and simvastatin shows beneficial HDL effects in patients having high triglyceride levels (N. Hoogerbrugge et al., J. Internal Med., 241, 151-55 (1997)).  
       [0054] Sitostanol ester margarine and pravastatin combination therapy is described by H. Gylling et al. (J. Lipid Res., 37, 1776-85 (1996)). That therapy is reported to simultaneously inhibit cholesterol absorption and lower LDL cholesterol significantly in non-insulin-dependent diabetic men.  
       [0055] Brown et al. (New Eng. J. Med., 323 (19), 1289-1339 (1990)) describe a combination therapy of lovastatin and colestipol which reduces atherosclerotic lesion progression and increase lesion regression relative to lovastatin alone.  
       [0056] Scott (PCT Patent Application No. WO 99/11260) describes combinations of atorvastatin (an HMG CoA reductase inhibitor) with an antihypertensive agent for the treatment of angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia, and symptoms of cardiac risk.  
       [0057] Egan et al. (PCT Patent Application No. WO 96/40255) describe a combination therapy of an angiotension II antagonist and an epoxy-steroidal aldosterone antagonist. The epoxy-steroidal aldosterone antagonist in the Egan application includes eplerenone.  
       [0058] The above references show continuing need to find safe, effective agents for the prophylaxis or treatment of cardiovascular diseases.  
       SUMMARY OF THE INVENTION  
       [0059] To address the continuing need to find safe and effective agents for the prophylaxis and treatment of cardiovascular diseases, combination therapies of cardiovascular drugs are now reported.  
       [0060] Among its several embodiments, the present invention provides a combination therapy comprising the use of a first amount of an IBAT inhibitor and a second amount of another cardiovascular therapeutic useful in the prophylaxis or treatment of hyperlipidemia or atherosclerosis, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. For example one of the many embodiments of the present invention is a therapeutic composition comprising first amount of an IBAT inhibitor and a second amount of a microsomal triglyceride transfer protein inhibitor (MTP inhibitor), wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. The IBAT inhibitor in the embodiments of this invention is preferably a benzothiepine IBAT inhibitor. In another embodiment, the IBAT inhibitor can be a benzothiazepine IBAT inhibitor. In still another embodiment, the IBAT inhibitor can be a naphthalene IBAT inhibitor.  
       [0061] The present invention further provides a therapeutic composition comprising a first amount of an IBAT inhibitor and a second amount of a cholesterol absorption antagonist, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
       [0062] The present invention further provides a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
       [0063] In another embodiment, the present invention also includes a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antiobesity compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds. For example, the antiobesity compound can comprise orlistat. Orlistat is described in European Patent No. EP 0 129 748.  
       [0064] Among its several embodiments, the present invention further provides a combination comprising a first amount of an IBAT inhibitor and a second amount of another cardiovascular therapeutic useful in the prophylaxis or treatment of hyperlipidemia or atherosclerosis, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. For example one of the many embodiments of the present invention is a combination comprising therapeutic dosages of an IBAT inhibitor and a phytosterol. A preferred embodiment of the present invention is a combination comprising therapeutic dosages of a benzothiepine IBAT inhibitor and a phytosterol. In another preferred embodiment, the present invention embraces a combination comprising an IBAT inhibitor and a stanol.  
       [0065] A still further embodiment of the instant invention comprises the use of any of the cardiovascular combination therapies described herein for the prophylaxis or treatment of hypercholesterolemia or atherosclerosis.  
       [0066] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a microsomal triglyceride transfer protein inhibiting compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
       [0067] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a cholesterol absorption antagonist compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
       [0068] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount of the compounds.  
       [0069] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a phytosterol compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds. Preferably the phytosterol compound comprises a stanol.  
       [0070] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a microsomal triglyceride transfer protein inhibiting compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
       [0071] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a cholesterol absorption antagonist compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
       [0072] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of an antihypertensive compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
       [0073] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a phytosterol compound in a second unit dosage form; and container means for containing said first and second unit dosage forms. Preferably the phytosterol compound comprises a stanol.  
       [0074] Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.  
       DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0075] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.  
       [0076] The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.  
       a. Definitions  
       [0077] The following definitions are provided in order to aid the reader in understanding the detailed description of the present invention:  
       [0078] “Benzothiepine IBAT inhibitor” means an ileal bile acid transport inhibitor which comprises a therapeutic compound comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure or a 2,3,4,5-tetrahydro-1-benzothiepine 1-oxide structure.  
       [0079] “Benzothiazepine IBAT inhibitor” means an ileal bile acid transport inhibitor which comprises a therapeutic compound comprising a 2,3,4,5-tetrahydro-1-benzothi-4-azepine 1,1-dioxide structure or a 2,3,4,5-tetrahydro-1-benzothi-5-azepine 1,1-dioxide structure.  
       [0080] “Naphthalene IBAT inhibitor” means an ileal bile acid transport inhibitor which comprises a therapeutic compound comprising a substituted naphthalene structure.  
       [0081] “Nicotinic acid derivative” means a therapeutic compound comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions, and tautomers. Nicotinic acid derivatives include, for example, nicotinic acid (niacin), niceritrol, and acipimox.  
       [0082] A “phytosterol” means any steroid naturally or synthetically derived having about C 8  to about C 10  carbon aliphatic side chains at position 17, and at least one alcoholic hydroxyl group (Miller-Keane,  Encyclopedia  &amp;  Dictionary of Medicine, Nursing , &amp;  Allied Health,  5th ed.). As used herein, the term “phytosterol” includes stanols.  
       [0083] “Stanol” means a class of phytosterols having a 5α-saturation.  
       [0084] “Combination therapy” means the administration of two or more therapeutic agents to treat a hypertensive condition or a hyperlipidemic condition, for example atherosclerosis and hypercholesterolemia. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single dosage form having a fixed ratio of active ingredients or in multiple, separate dosage forms for each inhibitor agent. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the hypertensive condition or the hyperlipidemic condition.  
       [0085] The phrase “therapeutically effective” is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hypertensive condition or the hyperlipidemic condition.  
       [0086] “Therapeutic compound” means a compound useful in the prophylaxis or treatment of a hypertensive condition or a hyperlipidemic condition, including atherosclerosis and hypercholesterolemia.  
       b. Combinations  
       [0087] The combinations of the present invention will have a number of uses. For example, through dosage adjustment and medical monitoring, the individual dosages of the therapeutic compounds used in the combinations of the present invention will be lower than are typical for dosages of the therapeutic compounds when used in monotherapy. The dosage lowering will provide advantages including reduction of side effects of the individual therapeutic compounds when compared to the monotherapy. In addition, fewer side effects of the combination therapy compared with the monotherapies will lead to greater patient compliance with therapy regimens.  
       [0088] Another use of the present invention will be in combinations having complementary effects or complementary modes of action. For example, IBAT inhibitors frequently lower LDL lipoprotein but also lower HDL lipoprotein. In contrast, CETP inhibitors raise HDL. A therapeutic combination of an IBAT inhibitor and a CETP inhibitor will, when dosages are optimally adjusted, lower LDL yet maintain or raise HDL.  
       [0089] Compounds useful in the present invention encompass a wide range of therapeutic compounds. IBAT inhibitors useful in the present invention are disclosed in patent application no. PCT/US95/10863, herein incorporated by reference. More IBAT inhibitors are described in PCT/US97/04076, herein incorporated by reference. Still further IBAT inhibitors useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference. More IBAT inhibitor compounds useful in the present invention are described in WO 98/40375, herein incorporated by reference. Additional IBAT inhibitor compounds useful in the present invention are described in U.S. application Ser. No. 08/816,065, herein incorporated by reference. IBAT inhibitors of particular interest in the present invention are shown in Table 1, as well as the diastereomers, enantiomers, racemates, salts, and tautomers of the IBAT inhibitors of Table 1.  
                   TABLE 1                       Compound           Number   Structure                              B-1                                     B-2                                         (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1-4-benzothiazepine 1,1-dioxide               B-3                                     B-4                                     B-5                                     B-6                                     B-7                                     B-8                                     B-9                                     B-10                                     B-11                                     B-12                                     B-13                                     B-14                                     B-15                                     B-16                                     B-17                                     B-18                                     B-19                                     B-20                                     B-21                                     B-22                                     B-23                                     B-24                                     B-25                                     B-26                                     B-27                                     B-28                                     B-29                                     B-30                                     B-31                                     B-32                                     B-33                                     B-34                                     B-35                                     B-36                                     B-37                                     B-38                                     B-39                                        
 
       [0090] Individual CETP inhibitor compounds useful in the present invention are separately described in the following individual patent applications, each of which is herein incorporated by reference.  
       [0091] R9. U.S. patent application Ser. No. 60/101661.  
       [0092] R10. U.S. patent application Ser. No. 60/101711.  
       [0093] R11. U.S. patent application Ser. No. 60/101660.  
       [0094] R12. U.S. patent application Ser. No. 60/101664.  
       [0095] R13. U.S. patent application Ser. No. 60/101668.  
       [0096] R14. U.S. patent application Ser. No. 60/101662.  
       [0097] R15. U.S. patent application Ser. No. 60/101663.  
       [0098] R16. U.S. patent application Ser. No. 60/101669.  
       [0099] R17. U.S. patent application Ser. No. 60/101667.  
       [0100] R18. U.S. patent application Ser. No. 09/401,916.  
       [0101] R19. U.S. patent application Ser. No. 09/405,524.  
       [0102] R20. U.S. patent application Ser. No. 09/404,638.  
       [0103] R21. U.S. patent application Ser. No. 09/404,638.  
       [0104] R22. U.S. patent application Ser. No. 09/400,915.  
       [0105] R23. U.S. Pat. No. 5,932,587.  
       [0106] R24. U.S. Pat. No. 5,925,645.  
       [0107] CETP inhibitor compounds of particular interest in the present invention are shown in Table 2.  
                   TABLE 2                       Compound           Number   Structure                              C-1                                     C-2                                     C-3                                     C-4                                     C-5                                     C-6                                     C-7                                     C-8                                     C-9                                     C-10                                     C-11                                     C-12                                     C-13                                     C-14                                     C-15                                     C-16                                     C-17                                     C-18                                     C-19                                     C-20                                        
 
       [0108] Fibric acid derivatives useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Preferred fibric acid derivatives for the present invention are described in Table 4. The therapeutic compounds of Table 4 can be used in the present invention in a variety of forms, including acid form, salt form, racemates, enantiomers, zwitterions, and tautomers. The individual U.S. patents referenced in Table 4 are each herein incorporated by reference.  
                           TABLE 4                                   U.S. Patent                   Reference for       Compound       CAS Registry   Compound Per       Number   Common Name   Number   Se                  G-41   Clofibrate    637-07-0   3,262,850       G-70   Fenofibrate   49562-28-9   4,058,552       G-38   Ciprofibrate   52214-84-3   3,948,973       G-20   Bezafibrate   41859-67-0   3,781,328       G-78   Gemfibrozil   25182-30-1   3,674,836                  
 
       [0109] MTP inhibitor compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the MTP inhibitor compounds of particular interest for use in the present invention are shown in Table 4b. The therapeutic compounds of Table 4b can be used in the present invention in a variety of forms, including acid form, salt form, racemates, enantiomers, zwitterions, and tautomers. Descriptions of the therapeutic compounds of Table 4b can be found in  Science,  282, Oct. 23, 1998, pp. 751-754, herein incorporated by reference.  
                   TABLE 4b                       Compound           Number   Structure                              M-1                                     M-2                                     M-3                                     M-4                                     M-5                                     M-6                                     M-7                                     M-8                                     M-9                                        
 
       [0110] Cholesterol absorption antagonist compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the cholesterol absorption antagonist compounds of particular interest for use in the present invention are described in U.S. Pat. No. 5,767,115, herein incorporated by reference. Further cholesterol absorption antagonist compounds of particular interest for use in the present invention, and methods for making such cholesterol absorption antagonist compounds are described in U.S. Pat. No. 5,631,365, herein incorporated by reference. A particularly preferred cholesterol absorption antagonist for use in the combinations and methods of the present invention is SCH 58235 ([3R-[3α(S*),4β]]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone).  
       [0111] In another embodiment the present invention includes a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of a phytosterol compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds. A number of phytosterols are described by Ling and Jones in “Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects,”  Life Sciences,  57 (3), 195-206 (1995). Without limitation, some phytosterols of particular use in the the combination of the present invention are shown in Table 4c. Phytosterols are also referred to generally by Nes ( Physiology and Biochemistry of Sterols , American Oil Chemists&#39; Society, Champaign, Ill., 1991, Table 7-2). Especially preferred among the phytosterols for use in the combination of the present invention are saturated phytosterols or stanols. Additional stanols are also described by Nes (Id.) and are useful in the combination of the present invention. In the combination of the present invention, the phytosterol preferably comprises a stanol. In one preferred embodiment the stanol is campestanol. In another preferred embodiment the stanol is cholestanol. In another preferred embodiment the stanol is clionastanol. In another preferred embodiment the stanol is coprostanol. In another preferred embodiment the stanol is 22,23-dihydrobrassicastanol. In another preferred embodiment the stanol is epicholestanol. In another Preferred embodiment the stanol is fucostanol. In another preferred embodiment the stanol is stigmastanol. In the combination of the present invention, the IBAT inhibitor is preferably a benzothiazepine IBAT inhibitor. In one preferred embodiment, the benzothiazepine IBAT inhibitor is compound B-2. In another preferred embodiment, the benzothiazepine IBAT inhibitor is compound B-7. In yet another preferred embodiment, the IBAT inhibitor is a benzothiepine IBAT inhibitor. Each of the following benzothiepine IBAT inhibitors represents a separate preferred embodiment of the present invention.  
       [0112] B-1.  
       [0113] B-3.  
       [0114] B-4.  
       [0115] B-5.  
       [0116] B-6.  
       [0117] B-8.  
       [0118] B-9.  
       [0119] B-10.  
       [0120] B-11.  
       [0121] B-12.  
       [0122] B-13.  
       [0123] B-14.  
       [0124] B-15.  
       [0125] B-16.  
       [0126] B-17.  
       [0127] B-18.  
       [0128] B-19.  
       [0129] B-21.  
       [0130] B-22.  
       [0131] B-23.  
       [0132] B-24.  
       [0133] B-25.  
       [0134] B-26.  
       [0135] B-27.  
       [0136] B-28.  
       [0137] B-29.  
       [0138] B-30.  
       [0139] B-31.  
       [0140] B-32.  
       [0141] B-33.  
       [0142] B-34.  
       [0143] B-35.  
       [0144] B-36.  
       [0145] B-37.  
       [0146] B-38.  
       [0147] B-39.  
       [0148] In yet another preferred embodiment, the IBAT inhibitor is a naphthalene IBAT inhibitor, for example, compound B-20.  
                       TABLE 4c                       Compound               No.   Compound Structure   Compound Name                                  P-1                         Campesterol               P-2                         22-Dihydrobrassicasterol               P-3                         Brassicasterol               P-4                         Codisterol               P-5                         β-sitosterol               P-6                         α-sitosterol               P-7                         γ-sitosterol               P-8                         Clionasterol               P-9                         Poriferasterol               P-10                         Stigmasterol               P-11                         Isofucosterol               P-12                         Fucosterol               P-13                         Clerosterol               P-14                         Nervisterol               P-15                         Lathosterol               P-16                         Fungisterol               P-17                         Stellasterol               P-18                         Spinasterol               P-19                         Chondrillasterol               P-20                         Peposterol               P-21                         Avenasterol               P-22                         Isoavenasterol               P-23                         Fecosterol               P-24                         Cholestanol               P-25                         Campestanol               P-26                         24β-Ethylcholestanol               P-27                         24α-Ethyl-22-dehydrocholestanol               P-28                         24β-Ethyl-22-dehydrocholestanol               P-29                         24-Ethyl-24(25)-dehydrocholestanol               P-30                         24β-Ethyl-25-dehydrocholestanol               P-31                         24β-Ethyl-22,25-bisdehydrocholestanol               P-32                         24-Methylene-25-methylcholestanol               P-33                         24,24-Dimethylcholestanol               P-34                         24α-Ethylcholestan-3α-ol               P-35                         Pollinastanol               P-36                         24-Dehydropollinastanol               P-37                         24-α-Methylpollinastanol               P-38                         24-β-Methylpollinastanol               P-39                         24-Methylenepollinastanol               P-40                         24β-Methyl-25-dehydropollinastanol                  
 
       [0149] In another embodiment the present invention encompasses a therapeutic combination of an IBAT inhibitor and an antihypertensive agent. Hypertension is defined as persistently high blood pressure. Generally, adults are classified as being hypertensive when systolic blood pressure is persistently above 140 mmHg or when diastolic blood pressure is above 90 mmHg. Long-term risks for cardiovascular mortality increase in a direct relationship with persistent blood pressure. (E. Braunwald,  Heart Disease,  5th ed., W.B. Saunders &amp; Co., Philadelphia, 1997, pp. 807-823.) Blood pressure is a function of cardiac output and peripheral resistance of the vascular system and can be represented by the following equation: 
       
         BP=CO×PR 
       
       [0150] wherein BP is blood pressure, CO is cardiac output, and PR is peripheral resistance. (Id., p. 816.) Factors affecting peripheral resistance include obesity and/or functional constriction. Factors affecting cardiac output include venous constriction. Functional constriction of the blood vessels can be caused by a variety of factors including thickening of blood vessel walls resulting in diminishment of the inside diameter of the vessels. Another factor which affects systolic blood pressure is rigidity of the aorta (Id., p. 811.)  
       [0151] Hypertension and atherosclerosis or other hyperlipidemic conditions often coexist in a patient. It is possible that certain hyperlipidemic conditions such as atherosclerosis can have a direct or indirect affect on hypertension. For example, atherosclerosis frequently results in diminishment of the inside diameter of blood vessels. Furthermore, atherosclerosis frequently results in increased rigidity of blood vessels, including the aorta. Both diminished inside diameter of blood vessels and rigidity of blood vessels are factors which contribute to hypertension.  
       [0152] Myocardial infarction is the necrosis of heart muscle cells resulting from oxygen deprivation and is usually caused by an obstruction of the supply of blood to the affected tissue. For example, hyperlipidemia or hypercholesterolemia can cause the formation of atherosclerotic plaques which can cause obstruction of blood flow and thereby cause myocardial infarction. (Id., pp. 1185-1187.) Another major risk factor for myocardial infarction is hypertension. (Id., p. 815.) In other words, hypertension and hyperlipidemic conditions such as atherosclerosis or hypercholesterolemia work in concert to cause myocardial infarction.  
       [0153] Coronary heart disease is another disease which is caused or aggravated by multiple factors including hyperlipidemic conditions and hypertension. Control of both hyperlipidemic conditions and hypertension are important to control symptoms or disease progression of coronary heart disease.  
       [0154] Angina pectoris is acute chest pain which is caused by decreased blood supply to the heart. Decreased blood supply to the heart is known as myocardial ischemia. Angina pectoris can be the result of, for example, stenosis of the aorta, pulmonary stenosis, and ventricular hypertrophy. Some antihypertensive agents, for example amlodipine, control angina pectoris by reducing peripheral resistance.  
       [0155] It is now disclosed that a therapy which controls hypertension and which in combination controls hyperlipidemic conditions will reduce risk from cardiovascular disease or symptoms of heart disease, for example coronary heart disease, myocardial infarction, or angina pectoris. Therefore one embodiment of the present invention is directed to a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive agent compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
       [0156] Some antihypertensive agents useful in the present invention are shown in Table 5, without limitation. A wide variety of chemical structures are useful as antihypertensive agents in the combinations of the present invention and the agents can operate by a variety of mechanisms. For example, useful antihypertensive agents can include, without limitation, an andrenergic blocker, a mixed alpha/beta andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, an andrenergic stimulant, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker, a diuretic, or a vasodilator. Additional hypertensive agents useful in the present invention are described by R. Scott in U.S. Patent Application No. 60/057,276 (priority document for PCT Patent Application No. WO 99/11260), herein incorporated by reference.  
                               TABLE 5                       Com-                       pound   Antihypertensive       Number   Classification   Compound Name   Dosage                      N-1   andrenergic   phenoxybenzamine   1-250   mg/day           blocker       N-2   andrenergic   guanadrel   5-60   mg/day           blocker       N-3   andrenergic   guanethidine           blocker       N-4   andrenergic   reserpine           blocker       N-5   andrenergic   terazosin   0.1-60   mg/day           blocker       N-6   andrenergic   prazosin   0.5-75   mg/day           blocker       N-7   andrenergic   polythiazide   0.25-10   mg/day           blocker       N-8   andrenergic   methyldopa   100-4000   mg/day           stimulant       N-9   andrenergic   methyldopate   100-4000   mg/day           stimulant       N-10   andrenergic   clonidine   0.1-2.5   mg/day           stimulant       N-11   andrenergic   chlorthalidone   10-50   mg/day           stimulant       N-12   andrenergic   guanfacine   0.25-5   mg/day           stimulant       N-13   andrenergic   guanabenz   2-40   mg/day           stimulant       N-14   andrenergic   trimethaphan           stimulant       N-15   alpha/beta   carvedilol   6-25   mg bid           andrenergic           blocker       N-16   alpha/beta   labetalol   10-500   mg/day           andrenergic           blocker       N-17   beta andrenergic   propranolol   10-1000   mg/day           blocker       N-18   beta andrenergic   metoprolol   10-500   mg/day           blocker       N-19   alpha andrenergic   doxazosin   1-16   mg/day           blocker       N-20   alpha andrenergic   phentolamine           blocker       N-21   angiotensin   quinapril   1-250   mg/day           converting           enzyme           inhibitor       N-22   angiotensin   perindopril   1-25   mg/day           converting   erbumine           enzyme           inhibitor       N-23   angiotensin   ramipril   0.25-20   mg/day           converting           enzyme           inhibitor       N-24   angiotensin   captopril   6-50   mg bid           converting           or tid           enzyme           inhibitor       N-25   angiotensin   trandolapril   0.25-25   mg/day           converting           enzyme           inhibitor       N-26   angiotensin   fosinopril   2-80   mg/day           converting           enzyme           inhibitor       N-27   angiotensin   lisinopril   1-80   mg/day           converting           enzyme           inhibitor       N-28   angiotensin   moexipril   1-100   mg/day           converting           enzyme           inhibitor       N-29   angiotensin   enalapril   2.5-40   mg/day           converting           enzyme           inhibitor       N-30   angiotensin   benazepril   10-80   mg/day           converting           enzyme           inhibitor       N-31   angiotensin II   candesartan   2-32   mg/day           receptor   cilexetil           antagonist       N-32   angiotensin II   inbesartan           receptor           antagonist       N-33   angiotensin II   losartan   10-100   mg/day           receptor           antagonist       N-34   angiotensin II   valsartan   20-600   mg/day           receptor           antagonist       N-35   calcium channel   verapamil   100-600   mg/day           blocker       N-36   calcium channel   diltiazem   150-500   mg/day           blocker       N-37   calcium channel   nifedipine   1-200   mg/day           blocker       N-38   calcium channel   nimodipine   5-500   mg/day           blocker       N-39   calcium channel   delodipine           blocker       N-40   calcium channel   nicardipine   1-20   mg/hr i.v.;           blocker       5-100   mg/day                       oral       N-41   calcium channel   isradipine           blocker       N-42   calcium channel   amlodipine   2-10   mg/day           blocker       N-43   diuretic   hydrochlorothiazide   5-100   mg/day       N-44   diuretic   chlorothiazide   250-2000   mg bid                       or tid       N-45   diuretic   furosemide   5-1000   mg/day       N-46   diuretic   bumetanide       N-47   diuretic   ethacrynic acid   20-400   mg/day       N-48   diuretic   amiloride   1-20   mg/day       N-49   diuretic   triameterene       N-50   diuretic   spironolactone   5-1000   mg/day       N-51   diuretic   eplerenone   10-150   mg/day       N-52   vasodilator   hydralazine   5-300   mg/day       N-53   vasodilator   minoxidil   1-100   mg/day       N-54   vasodilator   diazoxide   1-3   mg/kg       N-55   vasodilator   nitroprusside                  
 
       [0157] Additional calcium channel blockers which are useful in the combinations of the present invention include, without limitation, those shown in Table 5a.  
                               TABLE 5a                                   Compound                   Number   Compound Name   Reference                          N-56   bepridil   U.S. Pat. No. 3,962,238 or                   U.S. Reissue No. 30,577           N-57   clentiazem   U.S. Pat. No. 4,567,175           N-58   diltiazem   U.S. Pat. No. 3,562,257           N-59   fendiline   U.S. Pat. No. 3,262,977           N-60   gallopamil   U.S. Pat. No. 3,261,859           N-61   mibefradil   U.S. Pat. No. 4,808,605           N-62   prenylamine   U.S. Pat. No. 3,152,173           N-63   semotiadil   U.S. Pat. No. 4,786,635           N-64   terodiline   U.S. Pat. No. 3,371,014           N-65   verapamil   U.S. Pat. No. 3,261,859           N-66   aranipine   U.S. Pat. No. 4,572,909           N-67   bamidipine   U.S. Pat. No. 4,220,649           N-68   benidipine   European Patent Application                   Publication No. 106,275           N-69   cilnidipine   U.S. Pat. No. 4,672,068           N-70   efonidipine   U.S. Pat. No. 4,885,284           N-71   elgodipine   U.S. Pat. No. 4,962,592           N-72   felodipine   U.S. Pat. No. 4,264,611           N-73   isradipine   U.S. Pat. No. 4,466,972           N-74   lacidipine   U.S. Pat. No. 4,801,599           N-75   lercanidipine   U.S. Pat. No. 4,705,797           N-76   manidipine   U.S. Pat. No. 4,892,875           N-77   nicardipine   U.S. Pat. No. 3,985,758           N-78   nifendipine   U.S. Pat. No. 3,485,847           N-79   nilvadipine   U.S. Pat. No. 4,338,322           N-80   nimodipine   U.S. Pat. No. 3,799,934           N-81   nisoldipine   U.S. Pat. No. 4,154,839           N-82   nitrendipine   U.S. Pat. No. 3,799,934           N-83   cinnarizine   U.S. Pat. No. 2,882,271           N-84   flunarizine   U.S. Pat. No. 3,773,939           N-85   lidoflazine   U.S. Pat. No. 3,267,104           N-86   lomerizine   U.S. Pat. No. 4,663,325           N-87   bencyclane   Hungarian Pat. No. 151,865           N-88   etafenone   German Patent No. 1,265,758           N-89   perhexiline   British Patent No. 1,025,578                      
 
       [0158] Additional ACE inhibitors which are useful in the combinations of the present invention include, without limitation, those shown in Table 5b.  
                               TABLE 5b                                   Compound                   Number   Compound Name   Reference                          N-90   alacepril   U.S. Pat. No. 4,248,883           N-91   benazepril   U.S. Pat. No. 4,410,520           N-92   captopril   U.S. Pat. Nos. 4,046,889                   and 4,105,776           N-93   ceronapril   U.S. Pat. No. 4,452,790           N-94   delapril   U.S. Pat. No. 4,385,051           N-95   enalapril   U.S. Pat. No. 4,374,829           N-96   fosinopril   U.S. Pat. No. 4,337,201           N-97   imadapril   U.S. Pat. No. 4,508,727           N-98   lisinopril   U.S. Pat. No. 4,555,502           N-99   moveltopril   Belgian Patent No. 893,553           N-100   perindopril   U.S. Pat. No. 4,508,729           N-101   quinapril   U.S. Pat. No. 4,344,949           N-102   ramipril   U.S. Pat. No. 4,587,258           N-103   spirapril   U.S. Pat. No. 4,470,972           N-104   temocapril   U.S. Pat. No. 4,699,905           N-105   trandolapril   U.S. Pat. No. 4,933,361                      
 
       [0159] Additional beta andrenergic blockers which are useful in the combinations of the present invention include, without limitation, those shown in Table 5C.  
                       TABLE 5c                       Compound               Number   Compound Name   Reference                  N-106   acebutolol   U.S. Pat. No. 3,857,952       N-107   alprenolol   Netherlands Patent               Application No. 6,605,692       N-108   amosulalol   U.S. Pat. No. 4,217,305       N-109   arotinolol   U.S. Pat. No. 3,932,400       N-110   atenolol   U.S. Pat. No. 3,663,607 or               3,836,671       N-111   befunolol   U.S. Pat. No. 3,853,923       N-112   betaxolol   U.S. Pat. No. 4,252,984       N-113   bevantolol   U.S. Pat. No. 3,857,981       N-114   bisoprolol   U.S. Pat. No. 4,171,370       N-115   bopindolol   U.S. Pat. No. 4,340,641       N-116   bucumolol   U.S. Pat. No. 3,663,570       N-117   bufetolol   U.S. Pat. No. 3,723,476       N-118   bufuralol   U.S. Pat. No. 3,929,836       N-119   bunitrolol   U.S. Pat. Nos. 3,940,489               and 3,961,071       N-120   buprandolol   U.S. Pat. No. 3,309,406       N-121   butiridine   French Patent No. 1,390,056           hydrochloride       N-122   butofilolol   U.S. Pat. No. 4,252,825       N-123   carazolol   German Patent No. 2,240,599       N-124   carteolol   U.S. Pat. No. 3,910,924       N-125   carvedilol   U.S. Pat. No. 4,503,067       N-126   celiprolol   U.S. Pat. No. 4,034,009       N-127   cetamolol   U.S. Pat. No. 4,059,622       N-128   cloranolol   German Patent No. 2,213,044       N-129   dilevalol   Clifton et al., Journal of               Medicinal Chemistry, 1982 25,               670       N-130   epanolol   European Patent Publication               Application No. 41,491       N-131   indenolol   U.S. Pat. No. 4,045,482       N-132   labetalol   U.S. Pat. No. 4,012,444       N-133   levobunolol   U.S. Pat. No. 4,463,176       N-134   mepindolol   Seeman et al., Helv. Chim.               Acta, 1971, 54, 241       N-135   metipranolol   Czechoslovakian Patent               Application No. 128,471       N-136   metoprolol   U.S. Pat. No. 3,873,600       N-137   moprolol   U.S. Pat. No. 3,501,769       N-138   nadolol   U.S. Pat. No. 3,935,267       N-139   nadoxolol   U.S. Pat. No. 3,819,702       N-140   nebivalol   U.S. Pat. No. 4,654,362       N-141   nipradilol   U.S. Pat. No. 4,394,382       N-142   oxprenolol   British Patent No. 1,077,603       N-143   perbutolol   U.S. Pat. No. 3,551,493       N-144   pindolol   Swiss Patent Nos. 469,002               and 472,404       N-145   practolol   U.S. Pat. No. 3,408,387       N-146   pronethalol   British Patent No. 909,357       N-147   propranolol   U.S. Pat. Nos. 3,337,628               and 3,520,919       N-148   sotalol   Uloth et al., Journal of               Medicinal Chemistry, 1966,               9, 88       N-149   sufinalol   German Patent No. 2,728,641       N-150   talindol   U.S. Pat. Nos. 3,935,259               and 4,038,313       N-151   tertatolol   U.S. Pat. No. 3,960,891       N-152   tilisolol   U.S. Pat. No. 4,129,565       N-153   timolol   U.S. Pat. No. 3,655,663       N-154   toliprolol   U.S. Pat. No. 3,432,545       N-155   xibenolol   U.S. Pat. No. 4,018,824                  
 
       [0160] Additional alpha andrenergic blockers which are useful in the combinations of the present invention include, without limitation, those shown in Table 5d.  
                               TABLE 5d                                   Compound                   Number   Compound Name   Reference                          N-156   amosulalol   U.S. Pat. No. 4,217,307           N-157   arotinolol   U.S. Pat. No. 3,932,400           N-158   dapiprazole   U.S. Pat. No. 4,252,721           N-159   doxazosin   U.S. Pat. No. 4,188,390           N-160   fenspirlde   U.S. Pat. No. 3,399,192           N-161   indoramin   U.S. Pat. No. 3,527,761           N-162   labetalol   U.S. Pat. No. 4,012,444           N-163   naftopidil   U.S. Pat. No. 3,997,666           N-164   nicergoline   U.S. Pat. No. 3,228,943           N-165   prazosin   U.S. Pat. No. 3,511,836           N-166   tamsulosin   U.S. Pat. No. 4,703,063           N-167   tolazoline   U.S. Pat. No. 2,161,938           N-168   trimazosin   U.S. Pat. No. 3,669,968           N-169   yohimbine   Raymond-Hamet, J. Pharm.                   Chim., 19, 209 (1934)                      
 
       [0161] Additional angiotensin II receptor antagonists which are useful in the combinations of the present invention include, without limitation, those shown in Table 5e.  
                               TABLE 5e                                   Compound                   Number   Compound Name   Reference                          N-170   candesartan   U.S. Pat. No. 5,196,444           N-171   eprosartan   U.S. Pat. No. 5,185,351           N-172   irbesartan   U.S. Pat. No. 5,270,317           N-173   losartan   U.S. Pat. No. 5,138,069           N-174   valsartan   U.S. Pat. No. 5,399,578                      
 
       [0162] Additional vasodilators which are useful in the combinations of the present invention include, without limitation, those shown in Table 5F.  
                               TABLE 5f                                   Compound                   Number   Compound Name   Reference                          N-175   aluminum   U.S. Pat. No. 2,970,082               nicotinate           N-176   amotriphene   U.S. Pat. No. 3,010,965           N-177   bamethan   Corrigan et al., Journal of                   the American Chemical                   Society, 1945, 67, 1894           N-178   bencyclane   Hungarian Patent No. 151,865           N-180   bendazol   J. Chem. Soc., 1968, 2426           N-181   benfurodil   U.S. Pat. No. 3,355,463               hemisuccinate           N-182   benziodarone   U.S. Pat. No. 3,012,042           N-183   betahistine   Walter et al.; Journal of                   the American Chemical                   Society, 1941, 63, 2771           N-184   bradykinin   Hamburg et al., Arch.                   Biochem. Biophys., 1958, 76,                   252           N-185   brovincamine   U.S. Pat. No. 4,146,643           N-186   bufeniode   U.S. Pat. No. 3,542,870           N-187   buflomedil   U.S. Pat. No. 3,895,030           N-188   butalamine   U.S. Pat. No. 3,338,899           N-189   cetiedil   French Patent No. 1,460,571           N-190   chloracizine   British Patent No. 740,932           N-191   chromonar   U.S. Pat. No. 3,282,938           N-192   ciclonicate   German Patent No. 1,910,481           N-194   cinepazide   Belgian Patent No. 730,345           N-195   cinnarizine   U.S. Pat. No. 2,882,271           N-197   citicoline   Kennedy et al., Journal of                   the American Chemical                   Society, 1955, 77, 250 or                   synthesized as disclosed in                   Kennedy, Journal of                   Biological Chemistry, 1956,                   222, 185           N-198   clobenfural   British Patent No. 1,160,925           N-199   clonitrate   see Annalen, 1870, 155, 165           N-200   cloricromen   U.S. Pat. No. 4,452,811           N-201   cyclandelate   U.S. Pat. No. 2,707,193           N-203   diisopropylamine   Neutralization of               dichloroacetate   dichloroacetic acid with                   diisopropyl amine           N-204   diisopropylamine   British Patent No. 862,248               dichloroacetate           N-205   dilazep   U.S. Pat. No. 3,532,685           N-206   dipyridamole   British Patent No. 807,826           N-207   droprenilamine   German Patent No. 2,521,113           N-208   ebumamonine   Hermann et al., Journal of                   the American Chemical                   Society, 1979, 101, 1540           N-209   efloxate   British Patent Nos. 803,372                   and 824,547           N-210   eledoisin   British Patent No. 984,810           N-211   erythrityl   May be prepared by nitration               tetranitrate   of erythritol according to                   methods well-known to those                   skilled in the art. See                   e.g., Merck Index.           N-212   etafenone   German Patent No. 1,265,758           N-213   fasudil   U.S. Pat. No. 4,678,783           N-214   fendiline   U.S. Pat. No. 3,262,977           N-215   fenoxedil   U.S. Pat. No. 3,818,021 or                   German Patent No. 1,964,712           N-217   floredil   German Patent No. 2,020,464           N-218   flunarizine   German Patent No. 1,929,330                   or French Patent No.                   2,014,487           N-219   flunarizine   U.S. Pat. No. 3,773,939           N-220   ganglefene   U.S.S.R. Patent No. 115,905           N-221   hepronicate   U.S. Pat. No. 3,384,642           N-222   hexestrol   U.S. Pat. No. 2,357,985           N-223   hexobendine   U.S. Pat. No. 3,267,103           N-224   ibudilast   U.S. Pat. No. 3,850,941           N-225   ifenprodil   U.S. Pat. No. 3,509,164           N-227   iloprost   U.S. Pat. No. 4,692,464           N-228   inositol   Badgett et al., Journal of               niacinate   the American Chemical                   Society, 1947, 69, 2907           N-229   isoxsuprine   U.S. Pat. No. 3,056,836           N-230   itramin tosylate   Swedish Patent No. 168,308           N-231   kallidin   Biochem. Biophys. Re&amp;                   Commun., 1961, 6, 210           N-232   kallikrein   German Patent No. 1,102,973           N-233   khellin   Baxter et al., Journal of                   the Chemical Society, 1949,                   S 30           N-234   lidofiazine   U.S. Pat. No. 3,267,104           N-235   lomerizine   U.S. Pat. No. 4,663,325           N-236   mannitol   may be prepared by the               hexanitrate   nitration of mannitol                   according to methods well-                   known to those skilled in                   the art           N-237   medibazine   U.S. Pat. No. 3,119,826           N-238   moxisylyte   German Patent No. 905,738           N-239   nafronyl   U.S. Pat. No. 3,334,096           N-241   nicametate   Blicke &amp; Jenner, J. Am.                   Chem. Soc., 64, 1722 (1942)           N-243   nicergoline   U.S. Pat. No. 3,228,943           N-245   nicofuranose   Swiss Patent No. 366,523           N-246   nimodipine   U.S. Pat. No. 3,799,934           N-247   nitroglycerin   Sobrero, Ann., 64, 398                   (1847)           N-248   nylidrin   U.S. Pat. Nos. 2,661,372                   and 2,661,373           N-249   papaverine   Goldberg, Chem. Prod. Chem.                   News, 1954, 17, 371           N-250   pentaerythritol   U.S. Pat. No. 2,370,437               tetranitrate           N-251   pentifylline   German Patent No. 860,217           N-253   pentoxifylline   U.S. Pat. No. 3,422,107           N-254   pentrinitrol   German Patent No. 638,422-3           N-255   perhexilline   British Patent No. 1,025,578           N-256   pimefylline   U.S. Pat. No. 3,350,400           N-257   piribedil   U.S. Pat. No. 3,299,067           N-258   prenylamine   U.S. Pat. No. 3,152,173           N-259   propatyl nitrate   French Patent No. 1,103,113           N-260   prostaglandin El   may be prepared by any of                   the methods referenced in                   the Merck Index, Twelfth                   Edition, Budaved, Ed., New                   Jersey, 1996, p. 1353           N-261   suloctidil   German Patent No. 2,334,404           N-262   tinofedrine   U.S. Pat. No. 3,563,997           N-263   tolazoline   U.S. Pat. No. 2,161,938           N-264   trapidil   East German Patent No.                   55,956           N-265   tricromyl   U.S. Pat. No. 2,769,015           N-266   trimetazidine   U.S. Pat. No. 3,262,852           N-267   trolnitrate   French Patent No. 984,523 or               phosphate   German Patent No. 830,955           N-268   vincamine   U.S. Pat. No. 3,770,724           N-269   vinpocetine   U.S. Pat. No. 4,035,750           N-270   viquidil   U.S. Pat. No. 2,500,444           N-271   visnadine   U.S. Pat. Nos. 2,816,118                   and 2,980,699           N-272   xanthinol   German Patent No. 1,102,750               niacinate   or Korbonits et al., Acta.                   Pharm. Hung., 1968, 38, 98                      
 
       [0163] Additional diuretics which are useful in the combinations of the present invention include, without limitation, those shown in Table 5g.  
                       TABLE 5g                       Compound               Nunber   Compound Name   Reference                  N-273   acetazolamide   U.S. Pat. No. 2,980,679       N-274   althiazide   British Patent No. 902,658       N-275   amanozine   Austrian Patent No. 168,063       N-276   ambuside   U.S. Pat. No. 3,188,329       N-277   amiloride   Belgian Patent No. 639,386       N-278   arbutin   Tschb&amp;habln, Annalen, 1930,               479, 303       N-279   azosemide   U.S. Pat. No. 3,665,002       N-280   bendroflumethiazide   U.S. Pat. No. 3,265,573       N-281   benzthiazide   McManus et al., 136th Am.               Soc. Meeting (Atlantic               City, September 1959).               Abstract of Papers, pp 13-O       N-282   benzylhydro-   U.S. Pat. No. 3,108,097           chlorothiazide       N-283   bumetanide   U.S. Pat. No. 3,634,583       N-284   butazolamide   British Patent No. 769,757       N-285   buthiazide   British Patent Nos. 861,367               and 885,078       N-286   chloraminophenamide   U.S. Pat. Nos. 2,809,194,               2,965,655 and 2,965,656       N-287   chlorazanil   Austrian Patent No. 168,063       N-288   chlorothiazide   U.S. Pat. Nos. 2,809,194               and 2,937,169       N-289   chlorthalidone   U.S. Pat. No. 3,055,904       N-290   clofenamide   Olivier, Rec. Trav. Chim.,               1918, 37, 307       N-291   clopamide   U.S. Pat. No. 3,459,756       N-292   clorexolone   U.S. Pat. No. 3,183,243       N-293   cyclopenthiazide   Belgian Patent No. 587,225       N-294   cyclothiazide   Whitehead et al., Journal               of Organic Chemistry, 1961,               26, 2814       N-295   disulfamide   British Patent No. 851,287       N-296   epithiazide   U.S. Pat. No. 3,009,911       N-297   ethacrynic acid   U.S. Pat. No. 3,255,241       N-298   ethiazide   British Patent No. 861,367       N-299   ethoxolamide   British Patent No. 795,174       N-300   etozolin   U.S. Pat. No. 3,072,653       N-301   fenquizone   U.S. Pat. No. 3,870,720       N-302   furosemide   U.S. Pat. No. 3,058,882       N-303   hydracarbazine   British Patent No. 856,409       N-304   hydrochlorothiazide   U.S. Pat. No. 3,164,588       N-305   hydroflumethiazide   U.S. Pat. No. 3,254,076       N-306   indapamide   U.S. Pat. No. 3,565,911       N-307   isosorbide   U.S. Pat. No. 3,160,641       N-308   mannitol   U.S. Pat. No. 2,642,462;               or 2,749,371; or 2,759,024       N-309   mefruside   U.S. Pat. No. 3,356,692       N-310   methazolamide   U.S. Pat. No. 2,783,241       N-311   methyclothiazide   Close et al., Journal of               the American Chemical               Society, 1960, 82, 1132       N-312   meticrane   French Patent Nos. M2790               and 1,365,504       N-313   metochalcone   Freudenberg et al., Ber.,               1957, 90, 957       N-314   metolazone   U.S. Pat. No. 3,360,518       N-315   muzolimine   U.S. Pat. No. 4,018,890       N-316   paraflutizide   Belgian Patent No. 620,829       N-317   perhexiline   British Patent No.               1,025,578       N-318   piretanide   U.S. Pat. No. 4,010,273       N-319   polythiazide   U.S. Pat. No. 3,009,911       N-320   quinethazone   U.S. Pat. No. 2,976,289       N-321   teclothiazide   Close et al., Journal of               the American Chemical               Society, 1960, 82, 1132       N-322   ticrynafen   U.S. Pat. No. 3,758,506       N-323   torasemide   U.S. Pat. No. 4,018,929       N-324   triamterene   U.S. Pat. No. 3,081,230       N-325   trichlormethiazide   deStevens et al.,               Experientia, 1960, 16, 113       N-326   tripamide   Japanese Patent No. 73, 05,585       N-327   urea   Can be purchased from               commercial sources       N-328   xipamide   U.S. Pat. No. 3,567,777                  
 
       [0164] Many of the compounds useful in the present invention can have at least two asymmetric carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.  
       [0165] Isomers may include geometric isomers, for example cis-isomers or trans-isomers across a double bond. All such isomers are contemplated among the compounds useful in the present invention.  
       [0166] The compounds useful in the present invention also include tautomers.  
       [0167] The compounds useful in the present invention as discussed below include their salts, solvates and prodrugs.  
       Dosages, Formulations, and Routes of Administration  
       [0168] The compositions of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a human.  
       [0169] For the prophylaxis or treatment of the conditions referred to above, the compounds useful in the compositions and methods of the present invention can be used as the compound per se. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.  
       [0170] The anions useful in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.  
       [0171] The compounds useful in the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.  
       [0172] These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.  
       [0173] The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.  
       [0174] In general, a total daily dose of an IBAT inhibitor can be in the range of from about 0.01 to about 1000 mg/day, preferably from about 0.1 mg to about 50 mg/day, more preferably from about 1 to about 10 mg/day.  
       [0175] A total daily dose of a fibric acid derivative can generally be in the range of from about 1000 to about 3000 mg/day in single or divided doses. Gemfibrozil or clinofibrate, for example, are frequently each administered separately in a 1200 mg/day dose. Clofibrate is frequently administered in a 2000 mg/day dose. Binifibrate is frequently administered in a 1800 mg/day dose.  
       [0176] Generally a total daily dose of probucol can be in the range of from about 250 to about 2000 mg/day, preferably about 500 to about 1500 mg/day, and more preferably still about 750 to about 1000 mg/day in single or divided doses.  
       [0177] Generally a total daily dose of a nicotinic acid derivative can be in the range of from about 500 to about 10,000 mg/day, preferably about 1000 to about 8000 mg/day, and more preferably still about 3000 to about 6000 mg/day in single or divided doses.  
       [0178] For a CETP inhibitor, a daily dose of about 0.01 to about 100 mg/kg body weight/day, and preferably between about 0.5 to about 20 mg/kg body weight/day, may generally be appropriate.  
       [0179] For stanols, a daily dose of about 1000 to about 4000 mg/kg body weight/day, preferably between about 500 to about 1500 mg/kg body weight/day, and more preferably between about 150 to about 600 mg/kg body weight/day will generally be appropriate.  
       [0180] For antihypertensive agents, the daily dose will vary depending on the specific mechanism of activity, the chemistry of the antihypertensive agent, and the patient. General dose ranges for specific antihypertensive agents are described in Table 5 or in the Biological Assays section.  
       [0181] For cholesterol absorption antagonists, a daily dose of about 0.001 to about 500 mg/kg body weight/day, preferably between about 0.05 to about 300 mg/kg body weight/day, and more preferably between about 1 to about 200 mg/kg body weight/day will generally be appropriate.  
       [0182] For MTP inhibitors, a daily dose of about 0.001 to about 800 mg/kg body weight/day, preferably between about 0.01 to about 500 mg/kg body weight/day, more preferably between about 0.1 to about 300 mg/kg body weight/day, and more preferably still between about 1 to about 200 mg/kg body weight/day will generally be appropriate.  
       [0183] The daily doses described in the preceding paragraphs for the various therapeutic compounds can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.  
       [0184] In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.  
       [0185] Oral delivery of the combinations of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. For some of the therapeutic compounds useful in the present invention (e.g., IBAT inhibitors or CETP inhibitors), the intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (e.g., the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.  
       [0186] The combinations of the present invention can be delivered orally either in a solid, in a semi-solid, or in a liquid form. When in a liquid or in a semi-solid form, the combinations of the present invention can, for example, be in the form of a liquid, syrup, or contained in a gel capsule (e.g., a gel cap). In one embodiment, when a CETP inhibitor is used in a combination of the present invention, the CETP inhibitor can be provided in the form of a liquid, syrup, or contained in a gel capsule.  
       [0187] When administered intravenously, the dose for an IBAT inhibitor can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight.  
       [0188] For a CETP inhibitor the intravenously administered dose can, for example, be in the range of from about 0.003 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.01 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.1 mg/kg body weight to about 0.6 mg/kg body weight.  
       [0189] When administered intravenously, the dose for a fibric acid derivative can, for example, be in the range of from about 100 mg/kg body weight to about 2000 mg/kg body weight, preferably from about 300 mg/kg body weight to about 1000 mg/kg body weight, more preferably from about 400 mg/kg body weight to about 750 mg/kg body weight.  
       [0190] When administered intravenously, the dose for a nicotinic acid derivative can, for example, be in the range of from about 150 mg/kg body weight to about 3000 mg/kg body weight, preferably from about 300 mg/kg body weight to about 2000 mg/kg body weight, more preferably from about 500 mg/kg body weight to about 1000 mg/kg body weight.  
       [0191] The intravenously administered dose for probucol can, for example, be in the range of from about 50 mg/kg body weight to about 1500 mg/kg body weight, preferably from about 100 mg/kg body weight to about 1000 mg/kg body weight, more preferably from about 200 mg/kg body weight to about 750 mg/kg body weight.  
       [0192] The dose of any of these therapeutic compounds can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.  
       [0193] Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.  
       [0194] Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one therapeutic compound useful in the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent (s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.  
       [0195] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.  
       [0196] Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.  
       [0197] Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.  
       [0198] Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly (e.g., Vaseline), lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 50% w/w of the composition, for example, from 0.5 to 2%.  
       [0199] Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35% preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in  Pharmaceutical Research,  3(6), 318 (1986).  
       [0200] In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.  
       [0201] The solid dosage forms for oral administration including capsules, tablets, pills, powders, gel caps, and granules noted above comprise one or more compounds useful in the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate or solubilizing agents such as cyclodextrins. In the case of capsules, tablets, powders, granules, gel caps, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.  
       [0202] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.  
       [0203] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.  
       [0204] Pharmaceutically acceptable carriers encompass all the foregoing and the like.  
       [0205] In combination therapy, administration of two or more of the therapeutic agents useful in the present invention may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular, or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent.  
       [0206] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may with advantage contain one or more therapeutic compound in an amount described above. For example, in the case of an IBAT inhibitor, the dose range may be from about 0.01 mg/day to about 500 mg/day or any other dose, dependent upon the specific inhibitor, as is known in the art.  
       [0207] The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active therapeutic compound is one that achieves the same blood serum level as produced by oral administration as described above.  
       [0208] The therapeutic compounds may further be administered by any combination of oral/oral, oral/parenteral, or parenteral/parenteral route.  
       [0209] Pharmaceutical compositions for use in the treatment methods of the present invention may be administered in oral form or by intravenous administration. Oral administration of the combination therapy is preferred. Dosing for oral administration may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. The therapeutic compounds which make up the combination therapy may be administered simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The therapeutic compounds which make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step ingestion. Thus, a regimen may call for sequential administration of the therapeutic compounds with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range from a few minutes to several hours, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the patient. Circadian variation of the target molecule concentration may also determine the optimal dose interval. The therapeutic compounds of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one therapeutic compound by oral route and another therapeutic compound by intravenous route. Whether the therapeutic compounds of the combined therapy are administered by oral or intravenous route, separately or together, each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations components. Examples of suitable pharmaceutically-acceptable formulations containing the therapeutic compounds for oral administration are given above.  
       Treatment Regimen  
       [0210] The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.  
       [0211] Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum LDL and total cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of each type of therapeutic compound are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of the therapeutic compounds which together exhibit satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.  
       [0212] A potential advantage of the combination disclosed herein may be reduction of the amount of any individual therapeutic compound, or all therapeutic compounds, effective in treating hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia.  
       [0213] One of the several embodiments of the present invention provides a combination comprising the use of a first amount of an IBAT inhibitor and a second amount of another cardiovascular therapeutic useful in the prophylaxis or treatment of hyperlipidemia or atherosclerosis, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. For example one of the many embodiments of the present invention is a combination therapy comprising therapeutic dosages of an IBAT inhibitor and a CETP inhibitor. A preferred embodiment of the present invention is a combination therapy comprising therapeutic dosages of a benzothiepine IBAT inhibitor and a CETP inhibitor.  
       [0214] In another embodiment, the invention comprises a combination therapy comprising a first amount of an IBAT inhibitor and a second amount of a fibric acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. Still another embodiment comprises a combination therapy comprising a first amount of an IBAT inhibitor and a second amount of a nicotinic acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. The IBAT inhibitor in the embodiments of this paragraph is preferably a benzothiepine IBAT inhibitor.  
       [0215] Alternatively, an embodiment of the present invention provides a combination which comprises a first amount of a CETP inhibitor and a second amount of another cardiovascular therapeutic, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. A preferred embodiment provides a combination comprising a first amount of a CETP inhibitor and a second amount of a fibric acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. The invention is also embodied in a therapeutic composition comprising first amount of a CETP inhibitor and a second amount of a nicotinic acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. In the embodiments described in this paragraph, the CETP inhibitor is preferably the compound of formula C-1.  
       [0216] In another of its many embodiments, the present invention provides a combination comprising therapeutic dosages of an IBAT inhibitor and a phytosterol. In a preferred embodiment, the present invention provides a combination therapy comprising therapeutic dosages of a benzothiepine IBAT inhibitor and a phytosterol. In another preferred embodiment, the present invention provides a combination therapy comprising therapeutic dosages of an IBAT inhibitor and a stanol.  
       [0217] In another of its many embodiments, the present invention provides a combination comprising a first amount of an IBAT inhibitor and a second amount of a fibric acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds. In a preferred embodiment, the IBAT inhibitor is a benzothiepine IBAT inhibitor. In another preferred embodiment, the IBAT inhibitor is a benzothiazepine IBAT inhibitor. In yet another preferred embodiment, the IBAT inhibitor is a naphthalene IBAT inhibitor.  
       [0218] In another of its many embodiments, the present invention provides a combination comprising therapeutic dosages of an IBAT inhibitor and a cholesterol absorption antagonist. In a preferred embodiment, the present invention provides a combination therapy comprising therapeutic dosages of a benzothiepine IBAT inhibitor and a cholesterol absorption antagonist.  
       [0219] The embodiments of the present invention can comprise a combination therapy using two or more of the therapeutic compounds described or incorporated herein. The combination therapy can comprise two or more therapeutic compounds from different classes of chemistry, e.g., IBAT inhibitors can be therapeutically combined with CETP inhibitors. Therapeutic combinations can comprise more than two therapeutic compounds. For example, two or more therapeutic compounds from the same class of chemistry can comprise the therapy, e.g. a combination therapy comprising two or more IBAT inhibitors or two or more CETP inhibitors. In another embodiment the present invention provides a combination comprising two or more IBAT inhibitors or two or more stanols.  
       [0220] A further embodiment of the instant invention comprises the use of any of the cardiovascular combination therapies described herein for the prophylaxis or treatment of hypercholesterolemia or atherosclerosis.  
       [0221] The following non-limiting examples serve to illustrate various aspects of the present invention. 
     
    
    
     c. EXAMPLES  
     [0222] Table 6 illustrates examples of some of the many combinations of the present invention wherein the combination comprises a first amount of IBAT inhibitor and a second amount of a CETP inhibitor, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
                       TABLE 6                       Example               Number   Component 1   Component 2                                            1   B-1   C-1       2   B-1   C-2       3   B-1   C-3       4   B-1   C-4       5   B-1   C-5       6   B-1   C-6       7   B-1   C-7       8   B-1   C-8       9   B-1   C-9       10   B-1   C-10       11   B-1   C-11       12   B-1   C-12       13   B-1   C-13       14   B-1   C-14       15   B-1   C-15       16   B-1   C-16       17   B-1   C-17       18   B-1   C-18       19   B-1   C-19       20   B-1   C-20       21   B-2   C-1       22   B-2   C-2       23   B-2   C-3       24   B-2   C-4       25   B-2   C-5       26   B-2   C-6       27   B-2   C-7       28   B-2   C-8       29   B-2   C-9       30   B-2   C-10       31   B-2   C-11       32   B-2   C-12       33   B-2   C-13       34   B-2   C-14       35   B-2   C-15       36   B-2   C-16       37   B-2   C-17       38   B-2   C-18       39   B-2   C-19       40   B-2   C-20       41   B-3   C-1       42   B-3   C-2       43   B-3   C-3       44   B-3   C-4       45   B-3   C-5       46   B-3   C-6       47   B-3   C-7       48   B-3   C-8       49   B-3   C-9       50   B-3   C-10       51   B-3   C-11       52   B-3   C-12       53   B-3   C-13       54   B-3   C-14       55   B-3   C-15       56   B-3   C-16       57   B-3   C-17       58   B-3   C-18       59   B-3   C-19       60   B-3   C-20       61   B-4   C-1       62   B-4   C-2       63   B-4   C-3       64   B-4   C-4       65   B-4   C-5       66   B-4   C-6       67   B-4   C-7       68   B-4   C-8       69   B-4   C-9       70   B-4   C-10       71   B-4   C-11       72   B-4   C-12       73   B-4   C-13       74   B-4   C-14       75   B-4   C-15       76   B-4   C-16       77   B-4   C-17       78   B-4   C-18       79   B-4   C-19       80   B-4   C-20       81   B-5   C-1       82   B-5   C-2       83   B-5   C-3       84   B-5   C-4       85   B-5   C-5       86   B-5   C-6       87   B-5   C-7       88   B-5   C-8       89   B-5   C-9       90   B-5   C-10       91   B-5   C-11       92   B-5   C-12       93   B-5   C-13       94   B-5   C-14       95   B-5   C-15       96   B-5   C-16       97   B-5   C-17       98   B-5   C-18       99   B-5   C-19       100   B-5   C-20       101   B-6   C-1       102   B-6   C-2       103   B-6   C-3       104   B-6   C-4       105   B-6   C-5       106   B-6   C-6       107   B-6   C-7       108   B-6   C-8       109   B-6   C-9       110   B-6   C-10       111   B-6   C-11       112   B-6   C-12       113   B-6   C-13       114   B-6   C-14       115   B-6   C-15       116   B-6   C-16       117   B-6   C-17       118   B-6   C-18       119   B-6   C-19       120   B-6   C-20       121   B-7   C-1       122   B-7   C-2       123   B-7   C-3       124   B-7   C-4       125   B-7   C-5       126   B-7   C-6       127   B-7   C-7       128   B-7   C-8       129   B-7   C-9       130   B-7   C-10       131   B-7   C-11       132   B-7   C-12       133   B-7   C-13       134   B-7   C-14       135   B-7   C-15       136   B-7   C-16       137   B-7   C-17       138   B-7   C-18       139   B-7   C-19       140   B-7   C-20       141   B-8   C-1       142   B-8   C-2       143   B-8   C-3       144   B-8   C-4       145   B-8   C-5       146   B-8   C-6       147   B-8   C-7       148   B-8   C-8       149   B-8   C-9       150   B-8   C-10       151   B-8   C-11       152   B-8   C-12       153   B-8   C-13       154   B-8   C-14       155   B-8   C-15       156   B-8   C-16       157   B-8   C-17       158   B-8   C-18       159   B-8   C-19       160   B-8   C-20       161   B-9   C-1       162   B-9   C-2       163   B-9   C-3       164   B-9   C-4       165   B-9   C-5       166   B-9   C-6       167   B-9   C-7       168   B-9   C-8       169   B-9   C-9       170   B-9   C-10       171   B-9   C-11       172   B-9   C-12       173   B-9   C-13       174   B-9   C-14       175   B-9   C-15       176   B-9   C-16       177   B-9   C-17       178   B-9   C-18       179   B-9   C-19       180   B-9   C-20       181   B-10   C-1       182   B-10   C-2       183   B-10   C-3       184   B-10   C-4       185   B-10   C-5       186   B-10   C-6       187   B-10   C-7       188   B-10   C-8       189   B-10   C-9       190   B-10   C-10       191   B-10   C-11       192   B-10   C-12       193   B-10   C-13       194   B-10   C-14       195   B-10   C-15       196   B-10   C-16       197   B-10   C-17       198   B-10   C-18       199   B-10   C-19       200   B-10   C-20       201   B-11   C-1       202   B-11   C-2       203   B-11   C-3       204   B-11   C-4       205   B-11   C-5       206   B-11   C-6       207   B-11   C-7       208   B-11   C-8       209   B-11   C-9       210   B-11   C-10       211   B-11   C-11       212   B-11   C-12       213   B-11   C-13       214   B-11   C-14       215   B-11   C-15       216   B-11   C-16       217   B-11   C-17       218   B-11   C-18       219   B-11   C-19       220   B-11   C-20       221   B-12   C-1       222   B-12   C-2       223   B-12   C-3       224   B-12   C-4       225   B-12   C-5       226   B-12   C-6       227   B-12   C-7       228   B-12   C-8       229   B-12   C-9       230   B-12   C-10       231   B-12   C-11       232   B-12   C-12       233   B-12   C-13       234   B-12   C-14       235   B-12   C-15       236   B-12   C-16       237   B-12   C-17       238   B-12   C-18       239   B-12   C-19       240   B-12   C-20       241   B-13   C-1       242   B-13   C-2       243   B-13   C-3       244   B-13   C-4       245   B-13   C-5       246   B-13   C-6       247   B-13   C-7       248   B-13   C-8       249   B-13   C-9       250   B-13   C-10       251   B-13   C-11       252   B-13   C-12       253   B-13   C-13       254   B-13   C-14       255   B-13   C-15       256   B-13   C-16       257   B-13   C-17       258   B-13   C-18       259   B-13   C-19       260   B-13   C-20       261   B-14   C-1       262   B-14   C-2       263   B-14   C-3       264   B-14   C-4       265   B-14   C-5       266   B-14   C-6       267   B-14   C-7       268   B-14   C-8       269   B-14   C-9       270   B-14   C-10       271   B-14   C-11       272   B-14   C-12       273   B-14   C-13       274   B-14   C-14       275   B-14   C-15       276   B-14   C-16       277   B-14   C-17       278   B-14   C-18       279   B-14   C-19       280   B-14   C-20       281   B-15   C-1       282   B-15   C-2       283   B-15   C-3       284   B-15   C-4       285   B-15   C-5       286   B-15   C-6       287   B-15   C-7       288   B-15   C-8       289   B-15   C-9       290   B-15   C-10       291   B-15   C-11       292   B-15   C-12       293   B-15   C-13       294   B-15   C-14       295   B-15   C-15       296   B-15   C-16       297   B-15   C-17       298   B-15   C-18       299   B-15   C-19       300   B-15   C-20       301   B-16   C-1       302   B-16   C-2       303   B-16   C-3       304   B-16   C-4       305   B-16   C-5       306   B-16   C-6       307   B-16   C-7       308   B-16   C-8       309   B-16   C-9       310   B-16   C-10       311   B-16   C-11       312   B-16   C-12       313   B-16   C-13       314   B-16   C-14       315   B-16   C-15       316   B-16   C-16       317   B-16   C-17       318   B-16   C-18       319   B-16   C-19       320   B-16   C-20       321   B-17   C-1       322   B-17   C-2       323   B-17   C-3       324   B-17   C-4       325   B-17   C-5       326   B-17   C-6       327   B-17   C-7       328   B-17   C-8       329   B-17   C-9       330   B-17   C-10       331   B-17   C-11       332   B-17   C-12       333   B-17   C-13       334   B-17   C-14       335   B-17   C-15       336   B-17   C-16       337   B-17   C-17       338   B-17   C-18       339   B-17   C-19       340   B-17   C-20       341   B-18   C-1       342   B-18   C-2       343   B-18   C-3       344   B-18   C-4       345   B-18   C-5       346   B-18   C-6       347   B-18   C-7       348   B-18   C-8       349   B-18   C-9       350   B-18   C-10       351   B-18   C-11       352   B-18   C-12       353   B-18   C-13       354   B-18   C-14       355   B-18   C-15       356   B-18   C-16       357   B-18   C-17       358   B-18   C-18       359   B-18   C-19       360   B-18   C-20       361   B-19   C-1       362   B-19   C-2       363   B-19   C-3       364   B-19   C-4       365   B-19   C-5       366   B-19   C-6       367   B-19   C-7       368   B-19   C-8       369   B-19   C-9       370   B-19   C-10       371   B-19   C-11       372   B-19   C-12       373   B-19   C-13       374   B-19   C-14       375   B-19   C-15       376   B-19   C-16       377   B-19   C-17       378   B-19   C-18       379   B-19   C-19       380   B-19   C-20       381   B-20   C-1       382   B-20   C-2       383   B-20   C-3       384   B-20   C-4       385   B-20   C-5       386   B-20   C-6       387   B-20   C-7       388   B-20   C-8       389   B-20   C-9       390   B-20   C-10       391   B-20   C-11       392   B-20   C-12       393   B-20   C-13       394   B-20   C-14       395   B-20   C-15       396   B-20   C-16       397   B-20   C-17       398   B-20   C-18       399   B-20   C-19       400   B-20   C-20                  
 
     [0223] Table 8 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of an IBAT inhibitor and a second amount of a fibric acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
                       TABLE 8                       Example               Number   Component 1   Component 2                  601   B-1   clofibrate       602   B-2   clofibrate       603   B-3   clofibrate       604   B-4   clofibrate       605   B-5   clofibrate       606   B-6   clofibrate       607   B-7   clofibrate       608   B-8   clofibrate       609   B-9   clofibrate       610   B-10   clofibrate       611   B-11   clofibrate       612   B-12   clofibrate       613   B-13   clofibrate       614   B-14   clofibrate       615   B-15   clofibrate       616   B-16   clofibrate       617   B-17   clofibrate       618   B-18   clofibrate       619   B-19   clofibrate       620   B-20   clofibrate       621   B-1   fenofibrate       622   B-2   fenofibrate       623   B-3   fenofibrate       624   B-4   fenofibrate       625   B-5   fenofibrate       626   B-6   fenofibrate       627   B-7   fenofibrate       628   B-8   fenofibrate       629   B-9   fenofibrate       630   B-10   fenofibrate       631   B-11   fenofibrate       632   B-12   fenofibrate       633   B-13   fenofibrate       634   B-14   fenofibrate       635   B-15   fenofibrate       636   B-16   fenofibrate       637   B-17   fenofibrate       638   B-18   fenofibrate       639   B-19   fenofibrate       640   B-20   fenofibrate       641   B-1   ciprofibrate       642   B-2   ciprofibrate       643   B-3   ciprofibrate       644   B-4   ciprofibrate       645   B-5   ciprofibrate       646   B-6   ciprofibrate       647   B-7   ciprofibrate       648   B-8   ciprofibrate       649   B-9   ciprofibrate       650   B-10   ciprofibrate       651   B-11   ciprofibrate       652   B-12   ciprofibrate       653   B-13   ciprofibrate       654   B-14   ciprofibrate       655   B-15   ciprofibrate       656   B-16   ciprofibrate       657   B-17   ciprofibrate       658   B-18   ciprofibrate       659   B-19   ciprofibrate       660   B-20   ciprofibrate       661   B-1   bezafibrate       662   B-2   bezafibrate       663   B-3   bezafibrate       664   B-4   bezafibrate       665   B-5   bezafibrate       666   B-6   bezafibrate       667   B-7   bezafibrate       668   B-8   bezafibrate       669   B-9   bezafibrate       670   B-10   bezafibrate       671   B-11   bezafibrate       672   B-12   bezafibrate       673   B-13   bezafibrate       674   B-14   bezafibrate       675   B-15   bezafibrate       676   B-16   bezafibrate       677   B-17   bezafibrate       678   B-18   bezafibrate       679   B-19   bezafibrate       680   B-20   bezafibrate       681   B-1   gemfibrozil       682   B-2   gemfibrozil       683   B-3   gemfibrozil       684   B-4   gemfibrozil       685   B-5   gemfibrozil       686   B-6   gemfibrozil       687   B-7   gemfibrozil       688   B-8   gemfibrozil       689   B-9   gemfibrozil       690   B-10   gemfibrozil       691   B-11   gemfibrozil       692   B-12   gemfibrozil       693   B-13   gemfibrozil       694   B-14   gemfibrozil       695   B-15   gemfibrozil       696   B-16   gemfibrozil       697   B-17   gemfibrozil       698   B-18   gemfibrozil       699   B-19   gemfibrozil       700   B-20   gemfibrozil                  
 
     [0224] Table 10 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of an IBAT inhibitor and a second amount of a nicotinic acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
                       TABLE 10                       Example               Number   Component 1   Component 2                  901   B-1   nicotinic acid (niacin)       902   B-2   nicotinic acid (niacin)       903   B-3   nicotinic acid (niacin)       904   B-4   nicotinic acid (niacin)       905   B-5   nicotinic acid (niacin)       906   B-6   nicotinic acid (niacin)       907   B-7   nicotinic acid (niacin)       908   B-8   nicotinic acid (niacin)       909   B-9   nicotinic acid (niacin)       910   B-10   nicotinic acid (niacin)       911   B-11   nicotinic acid (niacin)       912   B-12   nicotinic acid (niacin)       913   B-13   nicotinic acid (niacin)       914   B-14   nicotinic acid (niacin)       915   B-15   nicotinic acid (niacin)       916   B-16   nicotinic acid (niacin)       917   B-17   nicotinic acid (niacin)       918   B-18   nicotinic acid (niacin)       919   B-19   nicotinic acid (niacin)       920   B-20   nicotinic acid (niacin)       921   B-1   niceritrol       922   B-2   niceritrol       923   B-3   niceritrol       924   B-4   niceritrol       925   B-5   niceritrol       926   B-6   niceritrol       927   B-7   niceritrol       928   B-8   niceritrol       929   B-9   niceritrol       930   B-10   niceritrol       931   B-11   niceritrol       932   B-12   niceritrol       933   B-13   niceritrol       934   B-14   niceritrol       935   B-15   niceritrol       936   B-16   niceritrol       937   B-17   niceritrol       938   B-18   niceritrol       939   B-19   niceritrol       940   B-20   niceritrol       941   B-1   acipimox       942   B-2   acipimox       943   B-3   acipimox       944   B-4   acipimox       945   B-5   acipimox       946   B-6   acipimox       947   B-7   acipimox       948   B-8   acipimox       949   B-9   acipimox       950   B-10   acipimox       951   B-11   acipimox       952   B-12   acipimox       953   B-13   acipimox       954   B-14   acipimox       955   B-15   acipimox       956   B-16   acipimox       957   B-17   acipimox       958   B-18   acipimox       959   B-19   acipimox       960   B-20   acipimox                  
 
     [0225] Table 13 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of a CETP inhibitor and a second amount of a fibric acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
                       TABLE 13                       Example               Number   Component 1   Component 2                  5601   C-1   clofibrate       5602   C-2   clofibrate       5603   C-3   clofibrate       5604   C-4   clofibrate       5605   C-5   clofibrate       5606   C-6   clofibrate       5607   C-7   clofibrate       5608   C-8   clofibrate       5609   C-9   clofibrate       5610   C-10   clofibrate       5611   C-11   clofibrate       5612   C-12   clofibrate       5613   C-13   clofibrate       5614   C-14   clofibrate       5615   C-15   clofibrate       5616   C-16   clofibrate       5617   C-17   clofibrate       5618   C-18   clofibrate       5619   C-19   clofibrate       5620   C-20   clofibrate       5621   C-1   fenofibrate       5622   C-2   fenofibrate       5623   C-3   fenofibrate       5624   C-4   fenofibrate       5625   C-5   fenofibrate       5626   C-6   fenofibrate       5627   C-7   fenofibrate       5628   C-8   fenofibrate       5629   C-9   fenofibrate       5630   C-10   fenofibrate       5631   C-11   fenofibrate       5632   C-12   fenofibrate       5633   C-13   fenofibrate       5634   C-14   fenofibrate       5635   C-15   fenofibrate       5636   C-16   fenofibrate       5637   C-17   fenofibrate       5638   C-18   fenofibrate       5639   C-19   fenofibrate       5640   C-20   fenofibrate       5641   C-1   ciprofibrate       5642   C-2   ciprofibrate       5643   C-3   ciprofibrate       5644   C-4   ciprofibrate       5645   C-5   ciprofibrate       5646   C-6   ciprofibrate       5647   C-7   ciprofibrate       5648   C-8   ciprofibrate       5649   C-9   ciprofibrate       5650   C-10   ciprofibrate       5651   C-11   ciprofibrate       5652   C-12   ciprofibrate       5653   C-13   ciprofibrate       5654   C-14   ciprofibrate       5655   C-15   ciprofibrate       5656   C-16   ciprofibrate       5657   C-17   ciprofibrate       5658   C-18   ciprofibrate       5659   C-19   ciprofibrate       5660   C-20   ciprofibrate       5661   C-1   bezafibrate       5662   C-2   bezafibrate       5663   C-3   bezafibrate       5664   C-4   bezafibrate       5665   C-5   bezafibrate       5666   C-6   bezafibrate       5667   C-7   bezafibrate       5668   C-8   bezafibrate       5669   C-9   bezafibrate       5670   C-10   bezafibrate       5671   C-11   bezafibrate       5672   C-12   bezafibrate       5673   C-13   bezafibrate       5674   C-14   bezafibrate       5675   C-15   bezafibrate       5676   C-16   bezafibrate       5677   C-17   bezafibrate       5678   C-18   bezafibrate       5679   C-19   bezafibrate       5680   C-20   bezafibrate       5681   C-1   gemfibrozil       5682   C-2   gemfibrozil       5683   C-3   gemfibrozil       5684   C-4   gemfibrozil       5685   C-5   gemfibrozil       5686   C-6   gemfibrozil       5687   C-7   gemfibrozil       5688   C-8   gemfibrozil       5689   C-9   gemfibrozil       5690   C-10   gemfibrozil       5691   C-11   gemfibrozil       5692   C-12   gemfibrozil       5693   C-13   gemfibrozil       5694   C-14   gemfibrozil       5695   C-15   gemfibrozil       5696   C-16   gemfibrozil       5697   C-17   gemfibrozil       5698   C-18   gemfibrozil       5699   C-19   gemfibrozil       5700   C-20   gemfibrozil                  
 
     [0226] Table 15 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of a CETP inhibitor and a second amount of a nicotinic acid derivative, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount or an anti-atherosclerotic condition effective amount of the compounds.  
                       TABLE 15                       Example               Number   Component 1   Component 2                  5901   C-1   nicotinic acid (niacin)       5902   C-2   nicotinic acid (niacin)       5903   C-3   nicotinic acid (niacin)       5904   C-4   nicotinic acid (niacin)       5905   C-5   nicotinic acid (niacin)       5906   C-6   nicotinic acid (niacin)       5907   C-7   nicotinic acid (niacin)       5908   C-8   nicotinic acid (niacin)       5909   C-9   nicotinic acid (niacin)       5910   C-10   nicotinic acid (niacin)       5911   C-11   nicotinic acid (niacin)       5912   C-12   nicotinic acid (niacin)       5913   C-13   nicotinic acid (niacin)       5914   C-14   nicotinic acid (niacin)       5915   C-15   nicotinic acid (niacin)       5916   C-16   nicotinic acid (niacin)       5917   C-17   nicotinic acid (niacin)       5918   C-18   nicotinic acid (niacin)       5919   C-19   nicotinic acid (niacin)       5920   C-20   nicotinic acid (niacin)       5921   C-1   niceritrol       5922   C-2   niceritrol       5923   C-3   niceritrol       5924   C-4   niceritrol       5925   C-5   niceritrol       5926   C-6   niceritrol       5927   C-7   niceritrol       5928   C-8   niceritrol       5929   C-9   niceritrol       5930   C-10   niceritrol       5931   C-11   niceritrol       5932   C-12   niceritrol       5933   C-13   niceritrol       5934   C-14   niceritrol       5935   C-15   niceritrol       5936   C-16   niceritrol       5937   C-17   niceritrol       5938   C-18   niceritrol       5939   C-19   niceritrol       5940   C-20   niceritrol       5941   C-1   acipimox       5942   C-2   acipimox       5943   C-3   acipimox       5944   C-4   acipimox       5945   C-5   acipimox       5946   C-6   acipimox       5947   C-7   acipimox       5948   C-8   acipimox       5949   C-9   acipimox       5950   C-10   acipimox       5951   C-11   acipimox       5952   C-12   acipimox       5953   C-13   acipimox       5954   C-14   acipimox       5955   C-15   acipimox       5956   C-16   acipimox       5957   C-17   acipimox       5958   C-18   acipimox       5959   C-19   acipimox       5960   C-20   acipimox                  
 
     [0227] Any of the MTP inhibitor compounds described by Wetterau et al. (Id.) can be used in combinations of the present invention wherein the combination comprises a first amount of an ileal bile acid transporter inhibiting compound and a second amount of a MTP inhibitor wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypertensive condition effective amount of the compounds. The IBAT inhibitor in the embodiments of this invention is preferably a benzothiepine IBAT inhibitor. In another preferred embodiment, the IBAT inhibitor is a benzothiazepine IBAT inhibitor. In still another preferred embodiment, the IBAT inhibitor is a naphthalene IBAT inhibitor. The IBAT inhibitor can, without limitation, be any one or combination of the compounds listed in Table 1.  
     [0228] Table 17 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of an ileal bile acid transporter inhibiting compound and a second amount of a cholesterol absorption antagonist wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, an anti-hypercholesterolemic condition effective amount, or an anti-hypertensive condition effective amount of the compounds. The IBAT inhibitor in the embodiments of this invention is preferably a benzothiepine IBAT inhibitor. In another preferred embodiment, the IBAT inhibitor is a benzothiazepine IBAT inhibitor. In still another preferred embodiment, the IBAT inhibitor is a naphthalene IBAT inhibitor. The IBAT inhibitor can, without limitation, be any one or combination of the compounds listed in Table 1. Preferably the cholesterol absorption antagonist is an azetidinone compound, and more preferably the cholesterol absorption antagonist is compound A-1.  
                       TABLE 16                       Example               Number   Compound 1   Compound 2                  7001   B-1   A-1       7002   B-2   A-1       7003   B-3   A-1       7004   B-4   A-1       7005   B-5   A-1       7006   B-6   A-1       7007   B-7   A-1       7008   B-8   A-1       7009   B-9   A-1       7010   B-10   A-1       7011   B-11   A-1       7012   B-12   A-1       7013   B-13   A-1       7014   B-14   A-1       7015   B-15   A-1       7016   B-16   A-1       7017   B-17   A-1       7018   B-18   A-1       7019   B-19   A-1       7020   B-20   A-1       7021   B-21   A-1       7022   B-22   A-1       7023   B-23   A-1       7024   B-24   A-1       7025   B-25   A-1       7026   B-26   A-1       7027   B-27   A-1       7028   B-28   A-1       7029   B-29   A-1       7030   B-30   A-1       7031   B-31   A-1       7032   B-32   A-1       7033   B-33   A-1       7034   B-34   A-1       7035   B-35   A-1       7036   B-36   A-1       7037   B-37   A-1       7038   B-38   A-1       7039   B-39   A-1                  
 
     [0229] Table 21 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of an ileal bile acid transporter inhibiting compound and a second amount of a cardiovascular therapeutic useful in the prophylaxis or treatment of hypertension, wherein the first and second amounts together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, an anti-hypercholesterolemic condition effective amount, or an anti-hypertensive condition effective amount of the compounds. The IBAT inhibitor in the embodiments of this invention is preferably a benzothiepine IBAT inhibitor. In another preferred embodiment, the IBAT inhibitor is a benzothiazepine IBAT inhibitor. In still another preferred embodiment, the IBAT inhibitor is a naphthalene IBAT inhibitor. The IBAT inhibitor can, without limitation, be any one or combination of the compounds listed in Table 1.  
                       TABLE 21                       Example               Number   Compound 1   Compound 2                  12000   amiloride   B-1       12001   amlodipine   B-1       12002   benazepril   B-1       12003   bumetanide   B-1       12004   candesartan cilexetil   B-1       12005   captopril   B-1       12006   carvedilol   B-1       12007   chlorothiazide   B-1       12008   chlorthalidone   B-1       12009   clonidine   B-1       12010   delodipine   B-1       12011   diazoxide   B-1       12012   diltiazem   B-1       12013   doxazosin   B-1       12014   enalapril   B-1       12015   eplerenone   B-1       12016   ethacrynic acid   B-1       12017   fosinopril   B-1       12018   furosemide   B-1       12019   guanabenz   B-1       12020   guanadrel   B-1       12021   guanethidine   B-1       12022   guanfacine   B-1       12023   hydralazine   B-1       12024   hydrochlorothiazide   B-1       12025   inbesartan   B-1       12026   isradipine   B-1       12027   labetalol   B-1       12028   lisinopril   B-1       12029   losartan   B-1       12030   methyldopa   B-1       12031   methyldopate   B-1       12032   metoprolol   B-1       12033   minoxidil   B-1       12034   moexipril   B-1       12035   nicardipine   B-1       12036   nifedipine   B-1       12037   nimodipine   B-1       12038   nitroprusside   B-1       12039   perindopril erbumine   B-1       12040   phenoxybenzamine   B-1       12041   phentolamine   B-1       12042   polythiazide   B-1       12043   prazosin   B-1       12044   propranolol   B-1       12045   quinapril   B-1       12046   ramipril   B-1       12047   reserpine   B-1       12048   spironolactone   B-1       12049   terazosin   B-1       12050   trandolapril   B-1       12051   triameterene   B-1       12052   trimethaphan   B-1       12053   valsartan   B-1       12054   verapamil   B-1       12055   amiloride   B-2       12056   amlodipine   B-2       12057   benazepril   B-2       12058   bumetanide   B-2       12059   candesartan cilexetil   B-2       12060   captopril   B-2       12061   carvedilol   B-2       12062   chlorothiazide   B-2       12063   chlorthalidone   B-2       12064   clonidine   B-2       12065   delodipine   B-2       12066   diazoxide   B-2       12067   diltiazem   B-2       12068   doxazosin   B-2       12069   enalapril   B-2       12070   eplerenone   B-2       12071   ethacrynic acid   B-2       12072   fosinopril   B-2       12073   furosemide   B-2       12074   guanabenz   B-2       12075   guanadrel   B-2       12076   guanethidine   B-2       12077   guanfacine   B-2       12078   hydralazine   B-2       12079   hydrochlorothiazide   B-2       12080   inbesartan   B-2       12081   isradipine   B-2       12082   labetalol   B-2       12083   lisinopril   B-2       12084   losartan   B-2       12085   methyldopa   B-2       12086   methyldopate   B-2       12087   metoprolol   B-2       12088   minoxidil   B-2       12089   moexipril   B-2       12090   nicardipine   B-2       12091   nifedipine   B-2       12092   nimodipine   B-2       12093   nitroprusside   B-2       12094   perindopril erbumine   B-2       12095   phenoxybenzamine   B-2       12096   phentolamine   B-2       12097   polythiazide   B-2       12098   prazosin   B-2       12099   propranolol   B-2       12100   quinapril   B-2       12101   ramipril   B-2       12102   reserpine   B-2       12103   spironolactone   B-2       12104   terazosin   B-2       12105   trandolapril   B-2       12106   triameterene   B-2       12107   trimethaphan   B-2       12108   valsartan   B-2       12109   verapamil   B-2       12110   amiloride   B-3       12111   amlodipine   B-3       12112   benazepril   B-3       12113   bumetanide   B-3       12114   candesartan cilexetil   B-3       12115   captopril   B-3       12116   carvedilol   B-3       12117   chlorothiazide   B-3       12118   chlorthalidone   B-3       12119   clonidine   B-3       12120   delodipine   B-3       12121   diazoxide   B-3       12122   diltiazem   B-3       12123   doxazosin   B-3       12124   enalapril   B-3       12125   eplerenone   B-3       12126   ethacrynic acid   B-3       12127   fosinopril   B-3       12128   furosemide   B-3       12129   guanabenz   B-3       12130   guanadrel   B-3       12131   guanethidine   B-3       12132   guanfacine   B-3       12133   hydralazine   B-3       12134   hydrochlorothiazide   B-3       12135   inbesartan   B-3       12136   isradipine   B-3       12137   labetalol   B-3       12138   lisinopril   B-3       12139   losartan   B-3       12140   methyldopa   B-3       12141   methyldopate   B-3       12142   metoprolol   B-3       12143   minoxidil   B-3       12144   moexipril   B-3       12145   nicardipine   B-3       12146   nifedipine   B-3       12147   nimodipine   B-3       12148   nitroprusside   B-3       12149   perindopril erbumine   B-3       12150   phenoxybenzamine   B-3       12151   phentolamine   B-3       12152   polythiazide   B-3       12153   prazosin   B-3       12154   propranolol   B-3       12155   quinapril   B-3       12156   ramipril   B-3       12157   reserpine   B-3       12158   spironolactone   B-3       12159   terazosin   B-3       12160   trandolapril   B-3       12161   triameterene   B-3       12162   trimethaphan   B-3       12163   valsartan   B-3       12164   verapamil   B-3       12165   amiloride   B-4       12166   amlodipine   B-4       12167   benazepril   B-4       12168   bumetanide   B-4       12169   candesartan cilexetil   B-4       12170   captopril   B-4       12171   carvedilol   B-4       12172   chlorothiazide   B-4       12173   chlorthalidone   B-4       12174   clonidine   B-4       12175   delodipine   B-4       12176   diazoxide   B-4       12177   diltiazem   B-4       12178   doxazosin   B-4       12179   enalapril   B-4       12180   eplerenone   B-4       12181   ethacrynic acid   B-4       12182   fosinopril   B-4       12183   furosemide   B-4       12184   guanabenz   B-4       12185   guanadrel   B-4       12186   guanethidine   B-4       12187   guanfacine   B-4       12188   hydralazine   B-4       12189   hydrochlorothiazide   B-4       12190   inbesartan   B-4       12191   isradipine   B-4       12192   labetalol   B-4       12193   lisinopril   B-4       12194   losartan   B-4       12195   methyldopa   B-4       12196   methyldopate   B-4       12197   metoprolol   B-4       12198   minoxidil   B-4       12199   moexipril   B-4       12200   nicardipine   B-4       12201   nifedipine   B-4       12202   nimodipine   B-4       12203   nitroprusside   B-4       12204   perindopril erbumine   B-4       12205   phenoxybenzamine   B-4       12206   phentolamine   B-4       12207   polythiazide   B-4       12208   prazosin   B-4       12209   propranolol   B-4       12210   quinapril   B-4       12211   ramipril   B-4       12212   reserpine   B-4       12213   spironolactone   B-4       12214   terazosin   B-4       12215   trandolapril   B-4       12216   triameterene   B-4       12217   trimethaphan   B-4       12218   valsartan   B-4       12219   verapamil   B-4       12220   amiloride   B-5       12221   amlodipine   B-5       12222   benazepril   B-5       12223   bumetanide   B-5       12224   candesartan cilexetil   B-5       12225   captopril   B-5       12226   carvedilol   B-5       12227   chlorothiazide   B-5       12228   chlorthalidone   B-5       12229   clonidine   B-5       12230   delodipine   B-5       12231   diazoxide   B-5       12232   diltiazem   B-5       12233   doxazosin   B-5       12234   enalapril   B-5       12235   eplerenone   B-5       12236   ethacrynic acid   B-5       12237   fosinopril   B-5       12238   furosemide   B-5       12239   guanabenz   B-5       12240   guanadrel   B-5       12241   guanethidine   B-5       12242   guanfacine   B-5       12243   hydralazine   B-5       12244   hydrochlorothiazide   B-5       12245   inbesartan   B-5       12246   isradipine   B-5       12247   labetalol   B-5       12248   lisinopril   B-5       12249   losartan   B-5       12250   methyldopa   B-5       12251   methyldopate   B-5       12252   metoprolol   B-5       12253   minoxidil   B-5       12254   moexipril   B-5       12255   nicardipine   B-5       12256   nifedipine   B-5       12257   nimodipine   B-5       12258   nitroprusside   B-5       12259   perindopril erbumine   B-5       12260   phenoxybenzamine   B-5       12261   phentolamine   B-5       12262   polythiazide   B-5       12263   prazosin   B-5       12264   propranolol   B-5       12265   quinapril   B-5       12266   ramipril   B-5       12267   reserpine   B-5       12268   spironolactone   B-5       12269   terazosin   B-5       12270   trandolapril   B-5       12271   triameterene   B-5       12272   trimethaphan   B-5       12273   valsartan   B-5       12274   verapamil   B-5       12275   amiloride   B-6       12276   amlodipine   B-6       12277   benazepril   B-6       12278   bumetanide   B-6       12279   candesartan cilexetil   B-6       12280   captopril   B-6       12281   carvedilol   B-6       12282   chlorothiazide   B-6       12283   chlorthalidone   B-6       12284   clonidine   B-6       12285   delodipine   B-6       12286   diazoxide   B-6       12287   diltiazem   B-6       12288   doxazosin   B-6       12289   enalapril   B-6       12290   eplerenone   B-6       12291   ethacrynic acid   B-6       12292   fosinopril   B-6       12293   furosemide   B-6       12294   guanabenz   B-6       12295   guanadrel   B-6       12296   guanethidine   B-6       12297   guanfacine   B-6       12298   hydralazine   B-6       12299   hydrochlorothiazide   B-6       12300   inbesartan   B-6       12301   isradipine   B-6       12302   labetalol   B-6       12303   lisinopril   B-6       12304   losartan   B-6       12305   methyldopa   B-6       12306   methyldopate   B-6       12307   metoprolol   B-6       12308   minoxidil   B-6       12309   moexipril   B-6       12310   nicardipine   B-6       12311   nifedipine   B-6       12312   nimodipine   B-6       12313   nitroprusside   B-6       12314   perindopril erbumine   B-6       12315   phenoxybenzamine   B-6       12316   phentolamine   B-6       12317   polythiazide   B-6       12318   prazosin   B-6       12319   propranolol   B-6       12320   quinapril   B-6       12321   ramipril   B-6       12322   reserpine   B-6       12323   spironolactone   B-6       12324   terazosin   B-6       12325   trandolapril   B-6       12326   triameterene   B-6       12327   trimethaphan   B-6       12328   valsartan   B-6       12329   verapamil   B-6       12330   amiloride   B-7       12331   amlodipine   B-7       12332   benazepril   B-7       12333   bumetanide   B-7       12334   candesartan cilexetil   B-7       12335   captopril   B-7       12336   carvedilol   B-7       12337   chlorothiazide   B-7       12338   chlorthalidone   B-7       12339   clonidine   B-7       12340   delodipine   B-7       12341   diazoxide   B-7       12342   diltiazem   B-7       12343   doxazosin   B-7       12344   enalapril   B-7       12345   eplerenone   B-7       12346   ethacrynic acid   B-7       12347   fosinopril   B-7       12348   furosemide   B-7       12349   guanabenz   B-7       12350   guanadrel   B-7       12351   guanethidine   B-7       12352   guanfacine   B-7       12353   hydralazine   B-7       12354   hydrochlorothiazide   B-7       12355   inbesartan   B-7       12356   isradipine   B-7       12357   labetalol   B-7       12358   lisinopril   B-7       12359   losartan   B-7       12360   methyldopa   B-7       12361   methyldopate   B-7       12362   metoprolol   B-7       12363   minoxidil   B-7       12364   moexipril   B-7       12365   nicardipine   B-7       12366   nifedipine   B-7       12367   nimodipine   B-7       12368   nitroprusside   B-7       12369   perindopril erbumine   B-7       12370   phenoxybenzamine   B-7       12371   phentolamine   B-7       12372   polythiazide   B-7       12373   prazosin   B-7       12374   propranolol   B-7       12375   quinapril   B-7       12376   ramipril   B-7       12377   reserpine   B-7       12378   spironolactone   B-7       12379   terazosin   B-7       12380   trandolapril   B-7       12381   triameterene   B-7       12382   trimethaphan   B-7       12383   valsartan   B-7       12384   verapamil   B-7       12385   amiloride   B-8       12386   amlodipine   B-8       12387   benazepril   B-8       12388   bumetanide   B-8       12389   candesartan cilexetil   B-8       12390   captopril   B-8       12391   carvedilol   B-8       12392   chlorothiazide   B-8       12393   chlorthalidone   B-8       12394   clonidine   B-8       12395   delodipine   B-8       12396   diazoxide   B-8       12397   diltiazem   B-8       12398   doxazosin   B-8       12399   enalapril   B-8       12400   eplerenone   B-8       12401   ethacrynic acid   B-8       12402   fosinopril   B-8       12403   furosemide   B-8       12404   guanabenz   B-8       12405   guanadrel   B-8       12406   guanethidine   B-8       12407   guanfacine   B-8       12408   hydralazine   B-8       12409   hydrochlorothiazide   B-8       12410   inbesartan   B-8       12411   isradipine   B-8       12412   labetalol   B-8       12413   lisinopril   B-8       12414   losartan   B-8       12415   methyldopa   B-8       12416   methyldopate   B-8       12417   metoprolol   B-8       12418   minoxidil   B-8       12419   moexipril   B-8       12420   nicardipine   B-8       12421   nifedipine   B-8       12422   nimodipine   B-8       12423   nitroprusside   B-8       12424   perindopril erbumine   B-8       12425   phenoxybenzamine   B-8       12426   phentolamine   B-8       12427   polythiazide   B-8       12428   prazosin   B-8       12429   propranolol   B-8       12430   quinapril   B-8       12431   ramipril   B-8       12432   reserpine   B-8       12433   spironolactone   B-8       12434   terazosin   B-8       12435   trandolapril   B-8       12436   triameterene   B-8       12437   trimethaphan   B-8       12438   valsartan   B-8       12439   verapamil   B-8       12440   amiloride   B-9       12441   amlodipine   B-9       12442   benazepril   B-9       12443   bumetanide   B-9       12444   candesartan cilexetil   B-9       12445   captopril   B-9       12446   carvedilol   B-9       12447   chlorothiazide   B-9       12448   chlorthalidone   B-9       12449   clonidine   B-9       12450   delodipine   B-9       12451   diazoxide   B-9       12452   diltiazem   B-9       12453   doxazosin   B-9       12454   enalapril   B-9       12455   eplerenone   B-9       12456   ethacrynic acid   B-9       12457   fosinopril   B-9       12458   furosemide   B-9       12459   guanabenz   B-9       12460   guanadrel   B-9       12461   guanethidine   B-9       12462   guanfacine   B-9       12463   hydralazine   B-9       12464   hydrochlorothiazide   B-9       12465   inbesartan   B-9       12466   isradipine   B-9       12467   labetalol   B-9       12468   lisinopril   B-9       12469   losartan   B-9       12470   methyldopa   B-9       12471   methyldopate   B-9       12472   metoprolol   B-9       12473   minoxidil   B-9       12474   moexipril   B-9       12475   nicardipine   B-9       12476   nifedipine   B-9       12477   nimodipine   B-9       12478   nitroprusside   B-9       12479   perindopril erbumine   B-9       12480   phenoxybenzamine   B-9       12481   phentolamine   B-9       12482   polythiazide   B-9       12483   prazosin   B-9       12484   propranolol   B-9       12485   quinapril   B-9       12486   ramipril   B-9       12487   reserpine   B-9       12488   spironolactone   B-9       12489   terazosin   B-9       12490   trandolapril   B-9       12491   triameterene   B-9       12492   trimethaphan   B-9       12493   valsartan   B-9       12494   verapamil   B-9       12495   amiloride   B-10       12496   amlodipine   B-10       12497   benazepril   B-10       12498   bumetanide   B-10       12499   candesartan cilexetil   B-10       12500   captopril   B-10       12501   carvedilol   B-10       12502   chlorothiazide   B-10       12503   chlorthalidone   B-10       12504   clonidine   B-10       12505   delodipine   B-10       12506   diazoxide   B-10       12507   diltiazem   B-10       12508   doxazosin   B-10       12509   enalapril   B-10       12510   eplerenone   B-10       12511   ethacrynic acid   B-10       12512   fosinopril   B-10       12513   furosemide   B-10       12514   guanabenz   B-10       12515   guanadrel   B-10       12516   guanethidine   B-10       12517   guanfacine   B-10       12518   hydralazine   B-10       12519   hydrochlorothiazide   B-10       12520   inbesartan   B-10       12521   isradipine   B-10       12522   labetalol   B-10       12523   lisinopril   B-10       12524   losartan   B-10       12525   methyldopa   B-10       12526   methyldopate   B-10       12527   metoprolol   B-10       12528   minoxidil   B-10       12529   moexipril   B-10       12530   nicardipine   B-10       12531   nifedipine   B-10       12532   nimodipine   B-10       12533   nitroprusside   B-10       12534   perindopril erbumine   B-10       12535   phenoxybenzamine   B-10       12536   phentolamine   B-10       12537   polythiazide   B-10       12538   prazosin   B-10       12539   propranolol   B-10       12540   quinapril   B-10       12541   ramipril   B-10       12542   reserpine   B-10       12543   spironolactone   B-10       12544   terazosin   B-10       12545   trandolapril   B-10       12546   triameterene   B-10       12547   trimethaphan   B-10       12548   valsartan   B-10       12549   verapamil   B-10       12550   amiloride   B-11       12551   amlodipine   B-11       12552   benazepril   B-11       12553   bumetanide   B-11       12554   candesartan cilexetil   B-11       12555   captopril   B-11       12556   carvedilol   B-11       12557   chlorothiazide   B-11       12558   chlorthalidone   B-11       12559   clonidine   B-11       12560   delodipine   B-11       12561   diazoxide   B-11       12562   diltiazem   B-11       12563   doxazosin   B-11       12564   enalapril   B-11       12565   eplerenone   B-11       12566   ethacrynic acid   B-11       12567   fosinopril   B-11       12568   furosemide   B-11       12569   guanabenz   B-11       12570   guanadrel   B-11       12571   guanethidine   B-11       12572   guanfacine   B-11       12573   hydralazine   B-11       12574   hydrochlorothiazide   B-11       12575   inbesartan   B-11       12576   isradipine   B-11       12577   labetalol   B-11       12578   lisinopril   B-11       12579   losartan   B-11       12580   methyldopa   B-11       12581   methyldopate   B-11       12582   metoprolol   B-11       12583   minoxidil   B-11       12584   moexipril   B-11       12585   nicardipine   B-11       12586   nifedipine   B-11       12587   nimodipine   B-11       12588   nitroprusside   B-11       12589   perindopril erbumine   B-11       12590   phenoxybenzamine   B-11       12591   phentolamine   B-11       12592   polythiazide   B-11       12593   prazosin   B-11       12594   propranolol   B-11       12595   quinapril   B-11       12596   ramipril   B-11       12597   reserpine   B-11       12598   spironolactone   B-11       12599   terazosin   B-11       12600   trandolapril   B-11       12601   triameterene   B-11       12602   trimethaphan   B-11       12603   valsartan   B-11       12604   verapamil   B-11       12605   amiloride   B-12       12606   amlodipine   B-12       12607   benazepril   B-12       12608   bumetanide   B-12       12609   candesartan cilexetil   B-12       12610   captopril   B-12       12611   carvedilol   B-12       12612   chlorothiazide   B-12       12613   chlorthalidone   B-12       12614   clonidine   B-12       12615   delodipine   B-12       12616   diazoxide   B-12       12617   diltiazem   B-12       12618   doxazosin   B-12       12619   enalapril   B-12       12620   eplerenone   B-12       12621   ethacrynic acid   B-12       12622   fosinopril   B-12       12623   furosemide   B-12       12624   guanabenz   B-12       12625   guanadrel   B-12       12626   guanethidine   B-12       12627   guanfacine   B-12       12628   hydralazine   B-12       12629   hydrochlorothiazide   B-12       12630   inbesartan   B-12       12631   isradipine   B-12       12632   labetalol   B-12       12633   lisinopril   B-12       12634   losartan   B-12       12635   methyldopa   B-12       12636   methyldopate   B-12       12637   metoprolol   B-12       12638   minoxidil   B-12       12639   moexipril   B-12       12640   nicardipine   B-12       12641   nifedipine   B-12       12642   nimodipine   B-12       12643   nitroprusside   B-12       12644   perindopril erbumine   B-12       12645   phenoxybenzamine   B-12       12646   phentolamine   B-12       12647   polythiazide   B-12       12648   prazosin   B-12       12649   propranolol   B-12       12650   quinapril   B-12       12651   ramipril   B-12       12652   reserpine   B-12       12653   spironolactone   B-12       12654   terazosin   B-12       12655   trandolapril   B-12       12656   triameterene   B-12       12657   trimethaphan   B-12       12658   valsartan   B-12       12659   verapamil   B-12       12660   amiloride   B-13       12661   amlodipine   B-13       12662   benazepril   B-13       12663   bumetanide   B-13       12664   candesartan cilexetil   B-13       12665   captopril   B-13       12666   carvedilol   B-13       12667   chlorothiazide   B-13       12668   chlorthalidone   B-13       12669   clonidine   B-13       12670   delodipine   B-13       12671   diazoxide   B-13       12672   diltiazem   B-13       12673   doxazosin   B-13       12674   enalapril   B-13       12675   eplerenone   B-13       12676   ethacrynic acid   B-13       12677   fosinopril   B-13       12678   furosemide   B-13       12679   guanabenz   B-13       12680   guanadrel   B-13       12681   guanethidine   B-13       12682   guanfacine   B-13       12683   hydralazine   B-13       12684   hydrochlorothiazide   B-13       12685   inbesartan   B-13       12686   isradipine   B-13       12687   labetalol   B-13       12688   lisinopril   B-13       12689   losartan   B-13       12690   methyldopa   B-13       12691   methyldopate   B-13       12692   metoprolol   B-13       12693   minoxidil   B-13       12694   moexipril   B-13       12695   nicardipine   B-13       12696   nifedipine   B-13       12697   nimodipine   B-13       12698   nitroprusside   B-13       12699   perindopril erbumine   B-13       12700   phenoxybenzamine   B-13       12701   phentolamine   B-13       12702   polythiazide   B-13       12703   prazosin   B-13       12704   propranolol   B-13       12705   quinapril   B-13       12706   ramipril   B-13       12707   reserpine   B-13       12708   spironolactone   B-13       12709   terazosin   B-13       12710   trandolapril   B-13       12711   triameterene   B-13       12712   trimethaphan   B-13       12713   valsartan   B-13       12714   verapamil   B-13       12715   amiloride   B-14       12716   amlodipine   B-14       12717   benazepril   B-14       12718   bumetanide   B-14       12719   candesartan cilexetil   B-14       12720   captopril   B-14       12721   carvedilol   B-14       12722   chlorothiazide   B-14       12723   chlorthalidone   B-14       12724   clonidine   B-14       12725   delodipine   B-14       12726   diazoxide   B-14       12727   diltiazem   B-14       12728   doxazosin   B-14       12729   enalapril   B-14       12730   eplerenone   B-14       12731   ethacrynic acid   B-14       12732   fosinopril   B-14       12733   furosemide   B-14       12734   guanabenz   B-14       12735   guanadrel   B-14       12736   guanethidine   B-14       12737   guanfacine   B-14       12738   hydralazine   B-14       12739   hydrochlorothiazide   B-14       12740   inbesartan   B-14       12741   isradipine   B-14       12742   labetalol   B-14       12743   lisinopril   B-14       12744   losartan   B-14       12745   methyldopa   B-14       12746   methyldopate   B-14       12747   metoprolol   B-14       12748   minoxidil   B-14       12749   moexipril   B-14       12750   nicardipine   B-14       12751   nifedipine   B-14       12752   nimodipine   B-14       12753   nitroprusside   B-14       12754   perindopril erbumine   B-14       12755   phenoxybenzamine   B-14       12756   phentolamine   B-14       12757   polythiazide   B-14       12758   prazosin   B-14       12759   propranolol   B-14       12760   quinapril   B-14       12761   ramipril   B-14       12762   reserpine   B-14       12763   spironolactone   B-14       12764   terazosin   B-14       12765   trandolapril   B-14       12766   triameterene   B-14       12767   trimethaphan   B-14       12768   valsartan   B-14       12769   verapamil   B-14       12770   amiloride   B-15       12771   amlodipine   B-15       12772   benazepril   B-15       12773   bumetanide   B-15       12774   candesartan cilexetil   B-15       12775   captopril   B-15       12776   carvedilol   B-15       12777   chlorothiazide   B-15       12778   chlorthalidone   B-15       12779   clonidine   B-15       12780   delodipine   B-15       12781   diazoxide   B-15       12782   diltiazem   B-15       12783   doxazosin   B-15       12784   enalapril   B-15       12785   eplerenone   B-15       12786   ethacrynic acid   B-15       12787   fosinopril   B-15       12788   furosemide   B-15       12789   guanabenz   B-15       12790   guanadrel   B-15       12791   guanethidine   B-15       12792   guanfacine   B-15       12793   hydralazine   B-15       12794   hydrochlorothiazide   B-15       12795   inbesartan   B-15       12796   isradipine   B-15       12797   labetalol   B-15       12798   lisinopril   B-15       12799   losartan   B-15       12800   methyldopa   B-15       12801   methyldopate   B-15       12802   metoprolol   B-15       12803   minoxidil   B-15       12804   moexipril   B-15       12805   nicardipine   B-15       12806   nifedipine   B-15       12807   nimodipine   B-15       12808   nitroprusside   B-15       12809   perindopril erbumine   B-15       12810   phenoxybenzamine   B-15       12811   phentolamine   B-15       12812   polythiazide   B-15       12813   prazosin   B-15       12814   propranolol   B-15       12815   quinapril   B-15       12816   ramipril   B-15       12817   reserpine   B-15       12818   spironolactone   B-15       12819   terazosin   B-15       12820   trandolapril   B-15       12821   triameterene   B-15       12822   trimethaphan   B-15       12823   valsartan   B-15       12824   verapamil   B-15       12825   amiloride   B-16       12826   amlodipine   B-16       12827   benazepril   B-16       12828   bumetanide   B-16       12829   candesartan cilexetil   B-16       12830   captopril   B-16       12831   carvedilol   B-16       12832   chlorothiazide   B-16       12833   chlorthalidone   B-16       12834   clonidine   B-16       12835   delodipine   B-16       12836   diazoxide   B-16       12837   diltiazem   B-16       12838   doxazosin   B-16       12839   enalapril   B-16       12840   eplerenone   B-16       12841   ethacrynic acid   B-16       12842   fosinopril   B-16       12843   furosemide   B-16       12844   guanabenz   B-16       12845   guanadrel   B-16       12846   guanethidine   B-16       12847   guanfacine   B-16       12848   hydralazine   B-16       12849   hydrochlorothiazide   B-16       12850   inbesartan   B-16       12851   isradipine   B-16       12852   labetalol   B-16       12853   lisinopril   B-16       12854   losartan   B-16       12855   methyldopa   B-16       12856   methyldopate   B-16       12857   metoprolol   B-16       12858   minoxidil   B-16       12859   moexipril   B-16       12860   nicardipine   B-16       12861   nifedipine   B-16       12862   nimodipine   B-16       12863   nitroprusside   B-16       12864   perindopril erbumine   B-16       12865   phenoxybenzamine   B-16       12866   phentolamine   B-16       12867   polythiazide   B-16       12868   prazosin   B-16       12869   propranolol   B-16       12870   quinapril   B-16       12871   ramipril   B-16       12872   reserpine   B-16       12873   spironolactone   B-16       12874   terazosin   B-16       12875   trandolapril   B-16       12876   triameterene   B-16       12877   trimethaphan   B-16       12878   valsartan   B-16       12879   verapamil   B-16       12880   amiloride   B-17       12881   amlodipine   B-17       12882   benazepril   B-17       12883   bumetanide   B-17       12884   candesartan cilexetil   B-17       12885   captopril   B-17       12886   carvedilol   B-17       12887   chlorothiazide   B-17       12888   chlorthalidone   B-17       12889   clonidine   B-17       12890   delodipine   B-17       12891   diazoxide   B-17       12892   diltiazem   B-17       12893   doxazosin   B-17       12894   enalapril   B-17       12895   eplerenone   B-17       12896   ethacrynic acid   B-17       12897   fosinopril   B-17       12898   furosemide   B-17       12899   guanabenz   B-17       12900   guanadrel   B-17       12901   guanethidine   B-17       12902   guanfacine   B-17       12903   hydralazine   B-17       12904   hydrochlorothiazide   B-17       12905   inbesartan   B-17       12906   isradipine   B-17       12907   labetalol   B-17       12908   lisinopril   B-17       12909   losartan   B-17       12910   methyldopa   B-17       12911   methyldopate   B-17       12912   metoprolol   B-17       12913   minoxidil   B-17       12914   moexipril   B-17       12915   nicardipine   B-17       12916   nifedipine   B-17       12917   nimodipine   B-17       12918   nitroprusside   B-17       12919   perindopril erbumine   B-17       12920   phenoxybenzamine   B-17       12921   phentolamine   B-17       12922   polythiazide   B-17       12923   prazosin   B-17       12924   propranolol   B-17       12925   quinapril   B-17       12926   ramipril   B-17       12927   reserpine   B-17       12928   spironolactone   B-17       12929   terazosin   B-17       12930   trandolapril   B-17       12931   triameterene   B-17       12932   trimethaphan   B-17       12933   valsartan   B-17       12934   verapamil   B-17       12935   amiloride   B-18       12936   amlodipine   B-18       12937   benazepril   B-18       12938   bumetanide   B-18       12939   candesartan cilexetil   B-18       12940   captopril   B-18       12941   carvedilol   B-18       12942   chlorothiazide   B-18       12943   chlorthalidone   B-18       12944   clonidine   B-18       12945   delodipine   B-18       12946   diazoxide   B-18       12947   diltiazem   B-18       12948   doxazosin   B-18       12949   enalapril   B-18       12950   eplerenone   B-18       12951   ethacrynic acid   B-18       12952   fosinopril   B-18       12953   furosemide   B-18       12954   guanabenz   B-18       12955   guanadrel   B-18       12956   guanethidine   B-18       12957   guanfacine   B-18       12958   hydralazine   B-18       12959   hydrochlorothiazide   B-18       12960   inbesartan   B-18       12961   isradipine   B-18       12962   labetalol   B-18       12963   lisinopril   B-18       12964   losartan   B-18       12965   methyldopa   B-18       12966   methyldopate   B-18       12967   metoprolol   B-18       12968   minoxidil   B-18       12969   moexipril   B-18       12970   nicardipine   B-18       12971   nifedipine   B-18       12972   nimodipine   B-18       12973   nitroprusside   B-18       12974   perindopril erbumine   B-18       12975   phenoxybenzamine   B-18       12976   phentolamine   B-18       12977   polythiazide   B-18       12978   prazosin   B-18       12979   propranolol   B-18       12980   quinapril   B-18       12981   ramipril   B-18       12982   reserpine   B-18       12983   spironolactone   B-18       12984   terazosin   B-18       12985   trandolapril   B-18       12986   triameterene   B-18       12987   trimethaphan   B-18       12988   valsartan   B-18       12989   verapamil   B-18       12990   amiloride   B-19       12991   amlodipine   B-19       12992   benazepril   B-19       12993   bumetanide   B-19       12994   candesartan cilexetil   B-19       12995   captopril   B-19       12996   carvedilol   B-19       12997   chlorothiazide   B-19       12998   chlorthalidone   B-19       12999   clonidine   B-19       13000   delodipine   B-19       13001   diazoxide   B-19       13002   diltiazem   B-19       13003   doxazosin   B-19       13004   enalapril   B-19       13005   eplerenone   B-19       13006   ethacrynic acid   B-19       13007   fosinopril   B-19       13008   furosemide   B-19       13009   guanabenz   B-19       13010   guanadrel   B-19       13011   guanethidine   B-19       13012   guanfacine   B-19       13013   hydralazine   B-19       13014   hydrochlorothiazide   B-19       13015   inbesartan   B-19       13016   isradipine   B-19       13017   labetalol   B-19       13018   lisinopril   B-19       13019   losartan   B-19       13020   methyldopa   B-19       13021   methyldopate   B-19       13022   metoprolol   B-19       13023   minoxidil   B-19       13024   moexipril   B-19       13025   nicardipine   B-19       13026   nifedipine   B-19       13027   nimodipine   B-19       13028   nitroprusside   B-19       13029   perindopril erbumine   B-19       13030   phenoxybenzamine   B-19       13031   phentolamine   B-19       13032   polythiazide   B-19       13033   prazosin   B-19       13034   propranolol   B-19       13035   quinapril   B-19       13036   ramipril   B-19       13037   reserpine   B-19       13038   spironolactone   B-19       13039   terazosin   B-19       13040   trandolapril   B-19       13041   triameterene   B-19       13042   trimethaphan   B-19       13043   valsartan   B-19       13044   verapamil   B-19       13045   amiloride   B-20       13046   amlodipine   B-20       13047   benazepril   B-20       13048   bumetanide   B-20       13049   candesartan cilexetil   B-20       13050   captopril   B-20       13051   carvedilol   B-20       13052   chlorothiazide   B-20       13053   chlorthalidone   B-20       13054   clonidine   B-20       13055   delodipine   B-20       13056   diazoxide   B-20       13057   diltiazem   B-20       13058   doxazosin   B-20       13059   enalapril   B-20       13060   eplerenone   B-20       13061   ethacrynic acid   B-20       13062   fosinopril   B-20       13063   furosemide   B-20       13064   guanabenz   B-20       13065   guanadrel   B-20       13066   guanethidine   B-20       13067   guanfacine   B-20       13068   hydralazine   B-20       13069   hydrochlorothiazide   B-20       13070   inbesartan   B-20       13071   isradipine   B-20       13072   labetalol   B-20       13073   lisinopril   B-20       13074   losartan   B-20       13075   methyldopa   B-20       13076   methyldopate   B-20       13077   metoprolol   B-20       13078   minoxidil   B-20       13079   moexipril   B-20       13080   nicardipine   B-20       13081   nifedipine   B-20       13082   nimodipine   B-20       13083   nitroprusside   B-20       13084   perindopril erbumine   B-20       13085   phenoxybenzamine   B-20       13086   phentolamine   B-20       13087   polythiazide   B-20       13088   prazosin   B-20       13089   propranolol   B-20       13090   quinapril   B-20       13091   ramipril   B-20       13092   reserpine   B-20       13093   spironolactone   B-20       13094   terazosin   B-20       13095   trandolapril   B-20       13096   triameterene   B-20       13097   trimethaphan   B-20       13098   valsartan   B-20       13099   verapamil   B-20       13100   amiloride   B-21       13101   amlodipine   B-21       13102   benazepril   B-21       13103   bumetanide   B-21       13104   candesartan cilexetil   B-21       13105   captopril   B-21       13106   carvedilol   B-21       13107   chlorothiazide   B-21       13108   chlorthalidone   B-21       13109   clonidine   B-21       13110   delodipine   B-21       13111   diazoxide   B-21       13112   diltiazem   B-21       13113   doxazosin   B-21       13114   enalapril   B-21       13115   eplerenone   B-21       13116   ethacrynic acid   B-21       13117   fosinopril   B-21       13118   furosemide   B-21       13119   guanabenz   B-21       13120   guanadrel   B-21       13121   guanethidine   B-21       13122   guanfacine   B-21       13123   hydralazine   B-21       13124   hydrochlorothiazide   B-21       13125   inbesartan   B-21       13126   isradipine   B-21       13127   labetalol   B-21       13128   lisinopril   B-21       13129   losartan   B-21       13130   methyldopa   B-21       13131   methyldopate   B-21       13132   metoprolol   B-21       13133   minoxidil   B-21       13134   moexipril   B-21       13135   nicardipine   B-21       13136   nifedipine   B-21       13137   nimodipine   B-21       13138   nitroprusside   B-21       13139   perindopril erbumine   B-21       13140   phenoxybenzamine   B-21       13141   phentolamine   B-21       13142   polythiazide   B-21       13143   prazosin   B-21       13144   propranolol   B-21       13145   quinapril   B-21       13146   ramipril   B-21       13147   reserpine   B-21       13148   spironolactone   B-21       13149   terazosin   B-21       13150   trandolapril   B-21       13151   triameterene   B-21       13152   trimethaphan   B-21       13153   valsartan   B-21       13154   verapamil   B-21       13155   amiloride   B-22       13156   amlodipine   B-22       13157   benazepril   B-22       13158   bumetanide   B-22       13159   candesartan cilexetil   B-22       13160   captopril   B-22       13161   carvedilol   B-22       13162   chlorothiazide   B-22       13163   chlorthalidone   B-22       13164   clonidine   B-22       13165   delodipine   B-22       13166   diazoxide   B-22       13167   diltiazem   B-22       13168   doxazosin   B-22       13169   enalapril   B-22       13170   eplerenone   B-22       13171   ethacrynic acid   B-22       13172   fosinopril   B-22       13173   furosemide   B-22       13174   guanabenz   B-22       13175   guanadrel   B-22       13176   guanethidine   B-22       13177   guanfacine   B-22       13178   hydralazine   B-22       13179   hydrochlorothiazide   B-22       13180   inbesartan   B-22       13181   isradipine   B-22       13182   labetalol   B-22       13183   lisinopril   B-22       13184   losartan   B-22       13185   methyldopa   B-22       13186   methyldopate   B-22       13187   metoprolol   B-22       13188   minoxidil   B-22       13189   moexipril   B-22       13190   nicardipine   B-22       13191   nifedipine   B-22       13192   nimodipine   B-22       13193   nitroprusside   B-22       13194   perindopril erbumine   B-22       13195   phenoxybenzamine   B-22       13196   phentolamine   B-22       13197   polythiazide   B-22       13198   prazosin   B-22       13199   propranolol   B-22       13200   quinapril   B-22       13201   ramipril   B-22       13202   reserpine   B-22       13203   spironolactone   B-22       13204   terazosin   B-22       13205   trandolapril   B-22       13206   triameterene   B-22       13207   trimethaphan   B-22       13208   valsartan   B-22       13209   verapamil   B-22       13210   amiloride   B-23       13211   amlodipine   B-23       13212   benazepril   B-23       13213   bumetanide   B-23       13214   candesartan cilexetil   B-23       13215   captopril   B-23       13216   carvedilol   B-23       13217   chlorothiazide   B-23       13218   chlorthalidone   B-23       13219   clonidine   B-23       13220   delodipine   B-23       13221   diazoxide   B-23       13222   diltiazem   B-23       13223   doxazosin   B-23       13224   enalapril   B-23       13225   eplerenone   B-23       13226   ethacrynic acid   B-23       13227   fosinopril   B-23       13228   furosemide   B-23       13229   guanabenz   B-23       13230   guanadrel   B-23       13231   guanethidine   B-23       13232   guanfacine   B-23       13233   hydralazine   B-23       13234   hydrochlorothiazide   B-23       13235   inbesartan   B-23       13236   isradipine   B-23       13237   labetalol   B-23       13238   lisinopril   B-23       13239   losartan   B-23       13240   methyldopa   B-23       13241   methyldopate   B-23       13242   metoprolol   B-23       13243   minoxidil   B-23       13244   moexipril   B-23       13245   nicardipine   B-23       13246   nifedipine   B-23       13247   nimodipine   B-23       13248   nitroprusside   B-23       13249   perindopril erbumine   B-23       13250   phenoxybenzamine   B-23       13251   phentolamine   B-23       13252   polythiazide   B-23       13253   prazosin   B-23       13254   propranolol   B-23       13255   quinapril   B-23       13256   ramipril   B-23       13257   reserpine   B-23       13258   spironolactone   B-23       13259   terazosin   B-23       13260   trandolapril   B-23       13261   triameterene   B-23       13262   trimethaphan   B-23       13263   valsartan   B-23       13264   verapamil   B-23       13265   amiloride   B-24       13266   amlodipine   B-24       13267   benazepril   B-24       13268   bumetanide   B-24       13269   candesartan cilexetil   B-24       13270   captopril   B-24       13271   carvedilol   B-24       13272   chlorothiazide   B-24       13273   chlorthalidone   B-24       13274   clonidine   B-24       13275   delodipine   B-24       13276   diazoxide   B-24       13277   diltiazem   B-24       13278   doxazosin   B-24       13279   enalapril   B-24       13280   eplerenone   B-24       13281   ethacrynic acid   B-24       13282   fosinopril   B-24       13283   furosemide   B-24       13284   guanabenz   B-24       13285   guanadrel   B-24       13286   guanethidine   B-24       13287   guanfacine   B-24       13288   hydralazine   B-24       13289   hydrochlorothiazide   B-24       13290   inbesartan   B-24       13291   isradipine   B-24       13292   labetalol   B-24       13293   lisinopril   B-24       13294   losartan   B-24       13295   methyldopa   B-24       13296   methyldopate   B-24       13297   metoprolol   B-24       13298   minoxidil   B-24       13299   moexipril   B-24       13300   nicardipine   B-24       13301   nifedipine   B-24       13302   nimodipine   B-24       13303   nitroprusside   B-24       13304   perindopril erbumine   B-24       13305   phenoxybenzamine   B-24       13306   phentolamine   B-24       13307   polythiazide   B-24       13308   prazosin   B-24       13309   propranolol   B-24       13310   quinapril   B-24       13311   ramipril   B-24       13312   reserpine   B-24       13313   spironolactone   B-24       13314   terazosin   B-24       13315   trandolapril   B-24       13316   triameterene   B-24       13317   trimethaphan   B-24       13318   valsartan   B-24       13319   verapamil   B-24       13320   amiloride   B-25       13321   amlodipine   B-25       13322   benazepril   B-25       13323   bumetanide   B-25       13324   candesartan cilexetil   B-25       13325   captopril   B-25       13326   carvedilol   B-25       13327   chlorothiazide   B-25       13328   chlorthalidone   B-25       13329   clonidine   B-25       13330   delodipine   B-25       13331   diazoxide   B-25       13332   diltiazem   B-25       13333   doxazosin   B-25       13334   enalapril   B-25       13335   eplerenone   B-25       13336   ethacrynic acid   B-25       13337   fosinopril   B-25       13338   furosemide   B-25       13339   guanabenz   B-25       13340   guanadrel   B-25       13341   guanethidine   B-25       13342   guanfacine   B-25       13343   hydralazine   B-25       13344   hydrochlorothiazide   B-25       13345   inbesartan   B-25       13346   isradipine   B-25       13347   labetalol   B-25       13348   lisinopril   B-25       13349   losartan   B-25       13350   methyldopa   B-25       13351   methyldopate   B-25       13352   metoprolol   B-25       13353   minoxidil   B-25       13354   moexipril   B-25       13355   nicardipine   B-25       13356   nifedipine   B-25       13357   nimodipine   B-25       13358   nitroprusside   B-25       13359   perindopril erbumine   B-25       13360   phenoxybenzamine   B-25       13361   phentolamine   B-25       13362   polythiazide   B-25       13363   prazosin   B-25       13364   propranolol   B-25       13365   quinapril   B-25       13366   ramipril   B-25       13367   reserpine   B-25       13368   spironolactone   B-25       13369   terazosin   B-25       13370   trandolapril   B-25       13371   triameterene   B-25       13372   trimethaphan   B-25       13373   valsartan   B-25       13374   verapamil   B-25       13375   amiloride   B-26       13376   amlodipine   B-26       13377   benazepril   B-26       13378   bumetanide   B-26       13379   candesartan cilexetil   B-26       13380   captopril   B-26       13381   carvedilol   B-26       13382   chlorothiazide   B-26       13383   chlorthalidone   B-26       13384   clonidine   B-26       13385   delodipine   B-26       13386   diazoxide   B-26       13387   diltiazem   B-26       13388   doxazosin   B-26       13389   enalapril   B-26       13390   eplerenone   B-26       13391   ethacrynic acid   B-26       13392   fosinopril   B-26       13393   furosemide   B-26       13394   guanabenz   B-26       13395   guanadrel   B-26       13396   guanethidine   B-26       13397   guanfacine   B-26       13398   hydralazine   B-26       13399   hydrochlorothiazide   B-26       13400   inbesartan   B-26       13401   isradipine   B-26       13402   labetalol   B-26       13403   lisinopril   B-26       13404   losartan   B-26       13405   methyldopa   B-26       13406   methyldopate   B-26       13407   metoprolol   B-26       13408   minoxidil   B-26       13409   moexipril   B-26       13410   nicardipine   B-26       13411   nifedipine   B-26       13412   nimodipine   B-26       13413   nitroprusside   B-26       13414   perindopril erbumine   B-26       13415   phenoxybenzamine   B-26       13416   phentolamine   B-26       13417   polythiazide   B-26       13418   prazosin   B-26       13419   propranolol   B-26       13420   quinapril   B-26       13421   ramipril   B-26       13422   reserpine   B-26       13423   spironolactone   B-26       13424   terazosin   B-26       13425   trandolapril   B-26       13426   triameterene   B-26       13427   trimethaphan   B-26       13428   valsartan   B-26       13429   verapamil   B-26       13430   amiloride   B-27       13431   amlodipine   B-27       13432   benazepril   B-27       13433   bumetanide   B-27       13434   candesartan cilexetil   B-27       13435   captopril   B-27       13436   carvedilol   B-27       13437   chlorothiazide   B-27       13438   chlorthalidone   B-27       13439   clonidine   B-27       13440   delodipine   B-27       13441   diazoxide   B-27       13442   diltiazem   B-27       13443   doxazosin   B-27       13444   enalapril   B-27       13445   eplerenone   B-27       13446   ethacrynic acid   B-27       13447   fosinopril   B-27       13448   furosemide   B-27       13449   guanabenz   B-27       13450   guanadrel   B-27       13451   guanethidine   B-27       13452   guanfacine   B-27       13453   hydralazine   B-27       13454   hydrochlorothiazide   B-27       13455   inbesartan   B-27       13456   isradipine   B-27       13457   labetalol   B-27       13458   lisinopril   B-27       13459   losartan   B-27       13460   methyldopa   B-27       13461   methyldopate   B-27       13462   metoprolol   B-27       13463   minoxidil   B-27       13464   moexipril   B-27       13465   nicardipine   B-27       13466   nifedipine   B-27       13467   nimodipine   B-27       13468   nitroprusside   B-27       13469   perindopril erbumine   B-27       13470   phenoxybenzamine   B-27       13471   phentolamine   B-27       13472   polythiazide   B-27       13473   prazosin   B-27       13474   propranolol   B-27       13475   quinapril   B-27       13476   ramipril   B-27       13477   reserpine   B-27       13478   spironolactone   B-27       13479   terazosin   B-27       13480   trandolapril   B-27       13481   triameterene   B-27       13482   trimethaphan   B-27       13483   valsartan   B-27       13484   verapamil   B-27       13485   amiloride   B-28       13486   amlodipine   B-28       13487   benazepril   B-28       13488   bumetanide   B-28       13489   candesartan cilexetil   B-28       13490   captopril   B-28       13491   carvedilol   B-28       13492   chlorothiazide   B-28       13493   chlorthalidone   B-28       13494   clonidine   B-28       13495   delodipine   B-28       13496   diazoxide   B-28       13497   diltiazem   B-28       13498   doxazosin   B-28       13499   enalapril   B-28       13500   eplerenone   B-28       13501   ethacrynic acid   B-28       13502   fosinopril   B-28       13503   furosemide   B-28       13504   guanabenz   B-28       13505   guanadrel   B-28       13506   guanethidine   B-28       13507   guanfacine   B-28       13508   hydralazine   B-28       13509   hydrochlorothiazide   B-28       13510   inbesartan   B-28       13511   isradipine   B-28       13512   labetalol   B-28       13513   lisinopril   B-28       13514   losartan   B-28       13515   methyldopa   B-28       13516   methyldopate   B-28       13517   metoprolol   B-28       13518   minoxidil   B-28       13519   moexipril   B-28       13520   nicardipine   B-28       13521   nifedipine   B-28       13522   nimodipine   B-28       13523   nitroprusside   B-28       13524   perindopril erbumine   B-28       13525   phenoxybenzamine   B-28       13526   phentolamine   B-28       13527   polythiazide   B-28       13528   prazosin   B-28       13529   propranolol   B-28       13530   quinapril   B-28       13531   ramipril   B-28       13532   reserpine   B-28       13533   spironolactone   B-28       13534   terazosin   B-28       13535   trandolapril   B-28       13536   triameterene   B-28       13537   trimethaphan   B-28       13538   valsartan   B-28       13539   verapamil   B-28       13540   amiloride   B-29       13541   amlodipine   B-29       13542   benazepril   B-29       13543   bumetanide   B-29       13544   candesartan cilexetil   B-29       13545   captopril   B-29       13546   carvedilol   B-29       13547   chlorothiazide   B-29       13548   chlorthalidone   B-29       13549   clonidine   B-29       13550   delodipine   B-29       13551   diazoxide   B-29       13552   diltiazem   B-29       13553   doxazosin   B-29       13554   enalapril   B-29       13555   eplerenone   B-29       13556   ethacrynic acid   B-29       13557   fosinopril   B-29       13558   furosemide   B-29       13559   guanabenz   B-29       13560   guanadrel   B-29       13561   guanethidine   B-29       13562   guanfacine   B-29       13563   hydralazine   B-29       13564   hydrochlorothiazide   B-29       13565   inbesartan   B-29       13566   isradipine   B-29       13567   labetalol   B-29       13568   lisinopril   B-29       13569   losartan   B-29       13570   methyldopa   B-29       13571   methyldopate   B-29       13572   metoprolol   B-29       13573   minoxidil   B-29       13574   moexipril   B-29       13575   nicardipine   B-29       13576   nifedipine   B-29       13577   nimodipine   B-29       13578   nitroprusside   B-29       13579   perindopril erbumine   B-29       13580   phenoxybenzamine   B-29       13581   phentolamine   B-29       13582   polythiazide   B-29       13583   prazosin   B-29       13584   propranolol   B-29       13585   quinapril   B-29       13586   ramipril   B-29       13587   reserpine   B-29       13588   spironolactone   B-29       13589   terazosin   B-29       13590   trandolapril   B-29       13591   triameterene   B-29       13592   trimethaphan   B-29       13593   valsartan   B-29       13594   verapamil   B-29       13595   amiloride   B-30       13596   amlodipine   B-30       13597   benazepril   B-30       13598   bumetanide   B-30       13599   candesartan cilexetil   B-30       13600   captopril   B-30       13601   carvedilol   B-30       13602   chlorothiazide   B-30       13603   chlorthalidone   B-30       13604   clonidine   B-30       13605   delodipine   B-30       13606   diazoxide   B-30       13607   diltiazem   B-30       13608   doxazosin   B-30       13609   enalapril   B-30       13610   eplerenone   B-30       13611   ethacrynic acid   B-30       13612   fosinopril   B-30       13613   furosemide   B-30       13614   guanabenz   B-30       13615   guanadrel   B-30       13616   guanethidine   B-30       13617   guanfacine   B-30       13618   hydralazine   B-30       13619   hydrochlorothiazide   B-30       13620   inbesartan   B-30       13621   isradipine   B-30       13622   labetalol   B-30       13623   lisinopril   B-30       13624   losartan   B-30       13625   methyldopa   B-30       13626   methyldopate   B-30       13627   metoprolol   B-30       13628   minoxidil   B-30       13629   moexipril   B-30       13630   nicardipine   B-30       13631   nifedipine   B-30       13632   nimodipine   B-30       13633   nitroprusside   B-30       13634   perindopril erbumine   B-30       13635   phenoxybenzamine   B-30       13636   phentolamine   B-30       13637   polythiazide   B-30       13638   prazosin   B-30       13639   propranolol   B-30       13640   quinapril   B-30       13641   ramipril   B-30       13642   reserpine   B-30       13643   spironolactone   B-30       13644   terazosin   B-30       13645   trandolapril   B-30       13646   triameterene   B-30       13647   trimethaphan   B-30       13648   valsartan   B-30       13649   verapamil   B-30       13650   amiloride   B-31       13651   amlodipine   B-31       13652   benazepril   B-31       13653   bumetanide   B-31       13654   candesartan cilexetil   B-31       13655   captopril   B-31       13656   carvedilol   B-31       13657   chlorothiazide   B-31       13658   chlorthalidone   B-31       13659   clonidine   B-31       13660   delodipine   B-31       13661   diazoxide   B-31       13662   diltiazem   B-31       13663   doxazosin   B-31       13664   enalapril   B-31       13665   eplerenone   B-31       13666   ethacrynic acid   B-31       13667   fosinopril   B-31       13668   furosemide   B-31       13669   guanabenz   B-31       13670   guanadrel   B-31       13671   guanethidine   B-31       13672   guanfacine   B-31       13673   hydralazine   B-31       13674   hydrochlorothiazide   B-31       13675   inbesartan   B-31       13676   isradipine   B-31       13677   labetalol   B-31       13678   lisinopril   B-31       13679   losartan   B-31       13680   methyldopa   B-31       13681   methyldopate   B-31       13682   metoprolol   B-31       13683   minoxidil   B-31       13684   moexipril   B-31       13685   nicardipine   B-31       13686   nifedipine   B-31       13687   nimodipine   B-31       13688   nitroprusside   B-31       13689   perindopril erbumine   B-31       13690   phenoxybenzamine   B-31       13691   phentolamine   B-31       13692   polythiazide   B-31       13693   prazosin   B-31       13694   propranolol   B-31       13695   quinapril   B-31       13696   ramipril   B-31       13697   reserpine   B-31       13698   spironolactone   B-31       13699   terazosin   B-31       13700   trandolapril   B-31       13701   triameterene   B-31       13702   trimethaphan   B-31       13703   valsartan   B-31       13704   verapamil   B-31       13705   amiloride   B-32       13706   amlodipine   B-32       13707   benazepril   B-32       13708   bumetanide   B-32       13709   candesartan cilexetil   B-32       13710   captopril   B-32       13711   carvedilol   B-32       13712   chlorothiazide   B-32       13713   chlorthalidone   B-32       13714   clonidine   B-32       13715   delodipine   B-32       13716   diazoxide   B-32       13717   diltiazem   B-32       13718   doxazosin   B-32       13719   enalapril   B-32       13720   eplerenone   B-32       13721   ethacrynic acid   B-32       13722   fosinopril   B-32       13723   furosemide   B-32       13724   guanabenz   B-32       13725   guanadrel   B-32       13726   guanethidine   B-32       13727   guanfacine   B-32       13728   hydralazine   B-32       13729   hydrochlorothiazide   B-32       13730   inbesartan   B-32       13731   isradipine   B-32       13732   labetalol   B-32       13733   lisinopril   B-32       13734   losartan   B-32       13735   methyldopa   B-32       13736   methyldopate   B-32       13737   metoprolol   B-32       13738   minoxidil   B-32       13739   moexipril   B-32       13740   nicardipine   B-32       13741   nifedipine   B-32       13742   nimodipine   B-32       13743   nitroprusside   B-32       13744   perindopril erbumine   B-32       13745   phenoxybenzamine   B-32       13746   phentolamine   B-32       13747   polythiazide   B-32       13748   prazosin   B-32       13749   propranolol   B-32       13750   quinapril   B-32       13751   ramipril   B-32       13752   reserpine   B-32       13753   spironolactone   B-32       13754   terazosin   B-32       13755   trandolapril   B-32       13756   triameterene   B-32       13757   trimethaphan   B-32       13758   valsartan   B-32       13759   verapamil   B-32       13760   amiloride   B-33       13761   amlodipine   B-33       13762   benazepril   B-33       13763   bumetanide   B-33       13764   candesartan cilexetil   B-33       13765   captopril   B-33       13766   carvedilol   B-33       13767   chlorothiazide   B-33       13768   chlorthalidone   B-33       13769   clonidine   B-33       13770   delodipine   B-33       13771   diazoxide   B-33       13772   diltiazem   B-33       13773   doxazosin   B-33       13774   enalapril   B-33       13775   eplerenone   B-33       13776   ethacrynic acid   B-33       13777   fosinopril   B-33       13778   furosemide   B-33       13779   guanabenz   B-33       13780   guanadrel   B-33       13781   guanethidine   B-33       13782   guanfacine   B-33       13783   hydralazine   B-33       13784   hydrochlorothiazide   B-33       13785   inbesartan   B-33       13786   isradipine   B-33       13787   labetalol   B-33       13788   lisinopril   B-33       13789   losartan   B-33       13790   methyldopa   B-33       13791   methyldopate   B-33       13792   metoprolol   B-33       13793   minoxidil   B-33       13794   moexipril   B-33       13795   nicardipine   B-33       13796   nifedipine   B-33       13797   nimodipine   B-33       13798   nitroprusside   B-33       13799   perindopril erbumine   B-33       13800   phenoxybenzamine   B-33       13801   phentolamine   B-33       13802   polythiazide   B-33       13803   prazosin   B-33       13804   propranolol   B-33       13805   quinapril   B-33       13806   ramipril   B-33       13807   reserpine   B-33       13808   spironolactone   B-33       13809   terazosin   B-33       13810   trandolapril   B-33       13811   triameterene   B-33       13812   trimethaphan   B-33       13813   valsartan   B-33       13814   verapamil   B-33       13815   amiloride   B-35       13816   amlodipine   B-35       13817   benazepril   B-35       13818   bumetanide   B-35       13819   candesartan cilexetil   B-35       13820   captopril   B-35       13821   carvedilol   B-35       13822   chlorothiazide   B-35       13823   chlorthalidone   B-35       13824   clonidine   B-35       13825   delodipine   B-35       13826   diazoxide   B-35       13827   diltiazem   B-35       13828   doxazosin   B-35       13829   enalapril   B-35       13830   eplerenone   B-35       13831   ethacrynic acid   B-35       13832   fosinopril   B-35       13833   furosemide   B-35       13834   guanabenz   B-35       13835   guanadrel   B-35       13836   guanethidine   B-35       13837   guanfacine   B-35       13838   hydralazine   B-35       13839   hydrochlorothiazide   B-35       13840   inbesartan   B-35       13841   isradipine   B-35       13842   labetalol   B-35       13843   lisinopril   B-35       13844   losartan   B-35       13845   methyldopa   B-35       13846   methyldopate   B-35       13847   metoprolol   B-35       13848   minoxidil   B-35       13849   moexipril   B-35       13850   nicardipine   B-35       13851   nifedipine   B-35       13852   nimodipine   B-35       13853   nitroprusside   B-35       13854   perindopril erbumine   B-35       13855   phenoxybenzamine   B-35       13856   phentolamine   B-35       13857   polythiazide   B-35       13858   prazosin   B-35       13859   propranolol   B-35       13860   quinapril   B-35       13861   ramipril   B-35       13862   reserpine   B-35       13863   spironolactone   B-35       13864   terazosin   B-35       13865   trandolapril   B-35       13866   triameterene   B-35       13867   trimethaphan   B-35       13868   valsartan   B-35       13869   verapamil   B-35       13870   amiloride   B-36       13871   amlodipine   B-36       13872   benazepril   B-36       13873   bumetanide   B-36       13874   candesartan cilexetil   B-36       13875   captopril   B-36       13876   carvedilol   B-36       13877   chlorothiazide   B-36       13878   chlorthalidone   B-36       13879   clonidine   B-36       13880   delodipine   B-36       13881   diazoxide   B-36       13882   diltiazem   B-36       13883   doxazosin   B-36       13884   enalapril   B-36       13885   eplerenone   B-36       13886   ethacrynic acid   B-36       13887   fosinopril   B-36       13888   furosemide   B-36       13889   guanabenz   B-36       13890   guanadrel   B-36       13891   guanethidine   B-36       13892   guanfacine   B-36       13893   hydralazine   B-36       13894   hydrochlorothiazide   B-36       13895   inbesartan   B-36       13896   isradipine   B-36       13897   labetalol   B-36       13898   lisinopril   B-36       13899   losartan   B-36       13900   methyldopa   B-36       13901   methyldopate   B-36       13902   metoprolol   B-36       13903   minoxidil   B-36       13904   moexipril   B-36       13905   nicardipine   B-36       13906   nifedipine   B-36       13907   nimodipine   B-36       13908   nitroprusside   B-36       13909   perindopril erbumine   B-36       13910   phenoxybenzamine   B-36       13911   phentolamine   B-36       13912   polythiazide   B-36       13913   prazosin   B-36       13914   propranolol   B-36       13915   quinapril   B-36       13916   ramipril   B-36       13917   reserpine   B-36       13918   spironolactone   B-36       13919   terazosin   B-36       13920   trandolapril   B-36       13921   triameterene   B-36       13922   trimethaphan   B-36       13923   valsartan   B-36       13924   verapamil   B-36       13925   amiloride   B-37       13926   amlodipine   B-37       13927   benazepril   B-37       13928   bumetanide   B-37       13929   candesartan cilexetil   B-37       13930   captopril   B-37       13931   carvedilol   B-37       13932   chlorothiazide   B-37       13933   chlorthalidone   B-37       13934   clonidine   B-37       13935   delodipine   B-37       13936   diazoxide   B-37       13937   diltiazem   B-37       13938   doxazosin   B-37       13939   enalapril   B-37       13940   eplerenone   B-37       13941   ethacrynic acid   B-37       13942   fosinopril   B-37       13943   furosemide   B-37       13944   guanabenz   B-37       13945   guanadrel   B-37       13946   guanethidine   B-37       13947   guanfacine   B-37       13948   hydralazine   B-37       13949   hydrochlorothiazide   B-37       13950   inbesartan   B-37       13951   isradipine   B-37       13952   labetalol   B-37       13953   lisinopril   B-37       13954   losartan   B-37       13955   methyldopa   B-37       13956   methyldopate   B-37       13957   metoprolol   B-37       13958   minoxidil   B-37       13959   moexipril   B-37       13960   nicardipine   B-37       13961   nifedipine   B-37       13962   nimodipine   B-37       13963   nitroprusside   B-37       13964   perindopril erbumine   B-37       13965   phenoxybenzamine   B-37       13966   phentolamine   B-37       13967   polythiazide   B-37       13968   prazosin   B-37       13969   propranolol   B-37       13970   quinapril   B-37       13971   ramipril   B-37       13972   reserpine   B-37       13973   spironolactone   B-37       13974   terazosin   B-37       13975   trandolapril   B-37       13976   triameterene   B-37       13977   trimethaphan   B-37       13978   valsartan   B-37       13979   verapamil   B-37       13980   amiloride   B-38       13981   amlodipine   B-38       13982   benazepril   B-38       13983   bumetanide   B-38       13984   candesartan cilexetil   B-38       13985   captopril   B-38       13986   carvedilol   B-38       13987   chlorothiazide   B-38       13988   chlorthalidone   B-38       13989   clonidine   B-38       13990   delodipine   B-38       13991   diazoxide   B-38       13992   diltiazem   B-38       13993   doxazosin   B-38       13994   enalapril   B-38       13995   eplerenone   B-38       13996   ethacrynic acid   B-38       13997   fosinopril   B-38       13998   furosemide   B-38       13999   guanabenz   B-38       14000   guanadrel   B-38       14001   guanethidine   B-38       14002   guanfacine   B-38       14003   hydralazine   B-38       14004   hydrochlorothiazide   B-38       14005   inbesartan   B-38       14006   isradipine   B-38       14007   labetalol   B-38       14008   lisinopril   B-38       14009   losartan   B-38       14010   methyldopa   B-38       14011   methyldopate   B-38       14012   metoprolol   B-38       14013   minoxidil   B-38       14014   moexipril   B-38       14015   nicardipine   B-38       14016   nifedipine   B-38       14017   nimodipine   B-38       14018   nitroprusside   B-38       14019   perindopril erbumine   B-38       14020   phenoxybenzamine   B-38       14021   phentolamine   B-38       14022   polythiazide   B-38       14023   prazosin   B-38       14024   propranolol   B-38       14025   quinapril   B-38       14026   ramipril   B-38       14027   reserpine   B-38       14028   spironolactone   B-38       14029   terazosin   B-38       14030   trandolapril   B-38       14031   triameterene   B-38       14032   trimethaphan   B-38       14033   valsartan   B-38       14034   verapamil   B-38       14035   amiloride   B-39       14036   amlodipine   B-39       14037   benazepril   B-39       14038   bumetanide   B-39       14039   candesartan cilexetil   B-39       14040   captopril   B-39       14041   carvedilol   B-39       14042   chlorothiazide   B-39       14043   chlorthalidone   B-39       14044   clonidine   B-39       14045   delodipine   B-39       14046   diazoxide   B-39       14047   diltiazem   B-39       14048   doxazosin   B-39       14049   enalapril   B-39       14050   eplerenone   B-39       14051   ethacrynic acid   B-39       14052   fosinopril   B-39       14053   furosemide   B-39       14054   guanabenz   B-39       14055   guanadrel   B-39       14056   guanethidine   B-39       14057   guanfacine   B-39       14058   hydralazine   B-39       14059   hydrochlorothiazide   B-39       14060   inbesartan   B-39       14061   isradipine   B-39       14062   labetalol   B-39       14063   lisinopril   B-39       14064   losartan   B-39       14065   methyldopa   B-39       14066   methyldopate   B-39       14067   metoprolol   B-39       14068   minoxidil   B-39       14069   moexipril   B-39       14070   nicardipine   B-39       14071   nifedipine   B-39       14072   nimodipine   B-39       14073   nitroprusside   B-39       14074   perindopril erbumine   B-39       14075   phenoxybenzamine   B-39       14076   phentolamine   B-39       14077   polythiazide   B-39       14078   prazosin   B-39       14079   propranolol   B-39       14080   quinapril   B-39       14081   ramipril   B-39       14082   reserpine   B-39       14083   spironolactone   B-39       14084   terazosin   B-39       14085   trandolapril   B-39       14086   triameterene   B-39       14087   trimethaphan   B-39       14088   valsartan   B-39       14089   verapamil   B-39                  
 
     [0230] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a microsomal triglyceride transfer protein inhibiting compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
     [0231] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a cholesterol absorption antagonist compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.  
     [0232] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount of the compounds.  
     [0233] In another embodiment the present invention provides a method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a phytosterol compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds. Preferably the phytosterol compound comprises a stanol.  
     [0234] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a microsomal triglyceride transfer protein inhibiting compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
     [0235] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a cholesterol absorption antagonist compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
     [0236] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of an antihypertensive compound in a second unit dosage form; and container means for containing said first and second unit dosage forms.  
     [0237] In another embodiment the present invention provides a kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form; an amount of a phytosterol compound in a second unit dosage form; and container means for containing said first and second unit dosage forms. Preferably the phytosterol compound comprises a stanol.  
     Biological Assays  
     [0238] The utility of the combinations of the present invention can be shown by the following assays. These assays are performed in vitro and in animal models essentially using procedures recognized to show the utility of the present invention.  
     [0239] In Vitro Assay of Compounds that Inhibit IBAT-mediated Uptake of [ 14 C]-Taurocholate (TC) in H14 Cells  
     [0240] Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are to be seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.  
     [0241] On the day of assay, the cell monolayer is gently washed once with 100 μl assay buffer (Dulbecco&#39;s Modified Eagle&#39;s medium with 4.5 g/L glucose+0.2% (w/v) fatty acid free bovine serum albumin-(FAF)BSA). To each well 50 μl of a two-fold concentrate of test compound in assay buffer is added along with 50 μl of 6 μM [ 14 C]-taurocholate in assay buffer (final concentration of 3 μM [ 14 C]-taurocholate). The cell culture plates are incubated 2 hours at 37° C. prior to gently washing each well twice with 100 μl 4° C. Dulbecco&#39;s phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then to be gently washed once with 100 μl 4° C. PBS without (FAF)BSA. To each 200 μl of liquid scintillation counting fluid is to be added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.  
     [0242] In Vitro Assay of Compounds that Inhibit uptake of [ 14 C]-Alanine  
     [0243] The alanine uptake assay can be performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is to be substituted for the labeled taurocholate.  
     [0244] In Vivo Assay of Compounds that Inhibit Rat Ileal Uptake of [ 14 C]-Taurocholate Into Bile  
     [0245] (See “Metabolism of 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid and 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters” in  Biochimica et Biophysica Acta,  833, 196-202 (1985) by Une et al., herein incorporated by reference.)  
     [0246] Male wistar rats (200-300 g) are to be anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10″ length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (⅛″ luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco&#39;s phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02″ I.D.×0.037″ O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is to be monitored continuously. At the start of the experiment, 2.0 ml of control sample ([ 14 C]-taurocholate @ 0.05 mCi/ml with 5 mM non-radiolabeled taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions will be collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second perfusion is to be initiated as described above but with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile to be sampled every 3 min for the first 27 min. If necessary, a third perfusion will be performed as above that typically contains the control sample.  
     [0247] Measurement of Hepatic Cholesterol Concentration (Hepatic CHOL)  
     [0248] Liver tissue is to be weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant is separated and dried under nitrogen. The residue is to be dissolved in isopropanol and the cholesterol content will be measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A. et al.,  Clin. Chem.,  20, 470 (1974) (herein incorporated by reference).  
     [0249] Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL+LDL)  
     [0250] Total serum cholesterol (SER.CHOL) are to be measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, Va.); Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) will be assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) will be assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL+LDL) cholesterol concentrations will be calculated as the difference between total and HDL cholesterol.  
     [0251] Measurement of Hepatic Cholesterol 7-α-Hydroxylase Activity (7a-OHase)  
     [0252] Hepatic microsomes are to be prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot will be assayed for cholesterol 7-α-hydroxylase activity by incubating for 5 minutes at 37° C. in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/methanol. The enzymatic product will be separated by injecting an aliquot of the extract onto a C 18  reversed phase HPLC column and quantitating the eluted material using UV detection at 240 nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).  
     [0253] Rat Gavage Assay  
     [0254] Male Wister rats (275-300 g) are to be administered IBAT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% TWEEN 80 in water) is administered once a day (9:00-10:0 a.m.) for 4 days at varying dosages in a final volume of 2 mL per kilogram of body weight. (TWEEN 80 is a 20 molar polyethyleneoxide sorbitan monooleate surfactant manufactured by ICI Specialty Chemicals, Wilmington, Del., U.S.A.) Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy will be determined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group.  
     [0255] Measurement of Fecal Bile Acid Concentration (FBA)  
     [0256] Total fecal output from individually housed rats is to be collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present will be measured enzymatically using the 3α-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (see Mashige, F. et al.  Clin. Chem.,  27, 1352 (1981), herein incorporated by reference).  
     [0257] [ 3 H]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV)  
     [0258] Rabbit Ileal brush border membranes are to be prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. ( Biochimica Biophysica Acta,  554, 259 (1979), herein incorporated by reference). The method for measuring taurocholate is essentially as described by Kramer et al. ( Biochimica Biophysica Acta,  1111, 93 (1992), herein incorporated by reference) except the assay volume will be 200 μl instead of 100 μl. Briefly, at room temperature a 190 μl solution containing 2 μl [ 3 H]-taurocholate(0.75 μCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 is incubated for 5 sec with 10 μl of brush border membrane vesicles (60-120 μg protein). The incubation is initiated by the addition of the BBMV while vortexing and the reaction is to be stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 μm pore) and an additional 5 ml wash with stop buffer.  
     [0259] Acyl-CoA; Cholesterol Acyl Transferase (ACAT)  
     [0260] Hamster liver and rat intestinal microsomes are to be prepared from tissue as described previously ( J. Biol. Chem.,  255, 9098 (1980), herein incorporated by reference) and used as a source of ACAT enzyme. The assay will consist of a 2.0 ml incubation containing 24 μl Oleoyl-CoA (0.05 μCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25% BSA and 200 μg of microsomal protein. The assay will be initiated by the addition of oleoyl-CoA. The reaction proceeds for 5 min at 37° C. and will be terminated by the addition of 8.0 ml of chloroform/methanol (2:1). To the extraction is added 125 μg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction are separated by centrifugation after thorough vortexing. The chloroform phase is to be taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed will be determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard Instaimager.  
     [0261] Dog Model for Evaluating Lipid Lowering Drugs  
     [0262] Male beagle dogs, obtained from a vendor such as Marshall farms and weighing 6-12 kg are fed once a day for two hours and given water ad libitum. Dogs may be randomly assigned to a dosing groups consisting of 6 to 12 dogs each, such as: vehicle, i.g.; 1 mg/kg, i.g.; 2 mg/kg, i.g.; 4 mg/kg, i.g.; 2 mg/kg, p.o. (powder in capsule). Intra-gastric dosing of a therapeutic material dissolved in aqueous solution (for example, 0.2% Tween 80 solution [polyoxyethylene mono-oleate, Sigma Chemical Co., St. Louis, Mo.]) may be done using a gavage tube. Prior to initiating dosing, blood samples may be drawn from the cephalic vein in the morning before feeding in order to evaluate serum cholesterol (total and HDL) and triglycerides. For several consecutive days animals are dosed in the morning, prior to feeding. Animals are to be allowed 2 hours to eat before any remaining food is removed. Feces are to be collected over a 2 day period at the end of the study and may be analyzed for bile acid or lipid content. Blood samples are also to be taken, at the end of the treatment period, for comparison with pre-study serum lipid levels. Statistical significance will be determined using the standard student&#39;s T-test with p&lt;0.05.  
     [0263] Dog Serum Lipid Measurement  
     [0264] Blood is to be collected from the cephalic vein of fasted dogs in serum separator tubes (Vacutainer SST, Becton Dickinson and Co., Franklin Lakes, N.J.). The blood is centrifuged at 2000 rpm for 20 minutes and the serum decanted.  
     [0265] Total cholesterol may be measured in a 96 well format using a Wako enzymatic diagnostic kit (Cholesterol CII) (Wako Chemicals, Richmond, Va.), utilizing the cholesterol oxidase reaction to produce hydrogen peroxide which is measured calorimetrically. A standard curve from 0.5 to 10 μg cholesterol is to be prepared in the first 2 columns of the plate. The serum samples (20-40 μl, depending on the expected lipid concentration) or known serum control samples are added to separate wells in duplicate. Water is added to bring the volume to 100 μl in each well. A 100 μl aliquot of color reagent is added to each well and the plates will be read at 500 nm after a 15 minute incubation at 37 degrees centigrade.  
     [0266] HDL cholesterol may be assayed using Sigma kit No. 352-3 (Sigma Chemical Co., St. Louis, Mo.) which utilizes dextran sulfate and Mg ions to selectively precipitate LDL and VLDL. A volume of 150 μl of each serum sample is to be added to individual microfuge tubes, followed by 15 μl of HDL cholesterol reagent (Sigma 352-3). Samples are to be mixed and centrifuged at 5000 rpm for 5 minutes. A 50 μl aliquot of the supernatant is to be then mixed with 200 μl of saline and assayed using the same procedure as for total cholesterol measurement.  
     [0267] Triglycerides are to be measured using Sigma kit No. 337 in a 96 well plate format. This procedure will measure glycerol, following its release by reaction of triglycerides with lipoprotein lipase. Standard solutions of glycerol (Sigma 339-11) ranging from 1 to 24 μg are to be used to generate the standard curve. Serum samples (20-40 μl, depending on the expected lipid concentration) are added to wells in duplicate. Water is added to bring the volume to 100 μl in each well and 100 μl of color reagent was also added to each well. After mixing and a 15 minute incubation, the plates will be read at 540 nm and the triglyceride values calculated from the standard curve. A replicate plate is also to be run using a blank enzyme reagent to correct for any endogenous glycerol in the serum samples.  
     [0268] Dog Fecal Bile Acid Measurement  
     [0269] Fecal samples may be collected to determine the fecal bile acid (FBA) concentration for each animal. Fecal collections may be made during the final 48 hours of the study, for two consecutive 24 hour periods between 9:00 am and 10:00 am each day, prior to dosing and feeding. The separate two day collections from each animal are to be weighed, combined and homogenized with distilled water in a processor (Cuisinart) to generate a homogeneous slurry. About 1.4 g of the homogenate is to be extracted in a final concentration of 50% tertiary butanol/distilled water (2:0.6) for 45 minutes in a 37° C. water bath and centrifuged for 13 minutes at 2000×g. The concentration of bile acids (mmoles/day) may be determined using a 96-well enzymatic assay system (1,2). A 20 μl aliquot of the fecal extract is to be added to two sets each of triplicate wells in a 96-well assay plate. A standardized sodium taurocholate solution and a standardized fecal extract solution (previously made from pooled samples and characterized for its bile acid concentration) will also analyzed for assay quality control. Twenty-microliter aliquots of sodium taurocholate, serially diluted to generate a standard curve are similarly to be added to two sets of triplicate wells. A 230 μl reaction mixture containing 1M hydrazine hydrate, 0.1 M pyrophosphate and 0.46 mg/ml NAD is to be added to each well. A 50 μl aliquot of 3a-hydroxysteroid dehydrogenase enzyme (HSD; 0.8 units/ml) or assay buffer (0.1 M sodium pyrophosphate) are then added to one of the two sets of triplicates. All reagents may be obtained from Sigma Chemical Co., St. Louis, Mo. Following 60 minutes of incubation at room temperature, the optical density at 340 nm will be measured and the mean of each set of triplicate samples will be calculated. The difference in optical density±HSD enzyme is to be used to determine the bile acid concentration (mM) of each sample based on the sodium taurocholate standard curve. The bile acid concentration of the extract, the weight of the fecal homogenate (grams) and the body weight of the animal are to be used to calculate the corresponding FBA concentration in mmoles/kg/day for each animal. The mean FBA concentration (mmoles/kg/day) of the vehicle group is to be subtracted from the FBA concentration of each treatment group to determine the increase (delta value) in FBA concentration as a result of the treatment.  
     [0270] Saponification and Extraction of Neutral Sterols in Hamster Feces  
     [0271] Generally, a sample of dried animal feces will be directly saponified with 0.3N KOH/Methanol for 1 hour. After saponification, the samples are filtered to remove solid matter. The samples are extracted twice with petroleum ether, and the extracts are combined and evaporated to dryness with heating under a stream of nitrogen gas. The sample can be analyzed by a Hewlett Packard Model 6890 GC with autosampler using a 50 meter HP-5 Ultra-2 capillary column, 0.33 um film thickness, 0.32 ID, 100:1 split ratio, and an FID detector.  
     [0272] For preparation of the saponified samples, each 0.25 gram sample of dried powdered feces is transferred to a labeled 20×150 millimeter screw top tube. Three milliliters of 0.3N KOH/MEOH (7.5 ml of 8N (45%) KOH qs 200 ml with HPLC grade methanol) and 25 microliters of 20 mg/ml 5-alpha Cholestane as the internal standard are added to the tubes. The tubes are tightly capped and vortexed. The tubes are placed in a Reacti-Therm heating block in a hood and heated at 70° C. for one hour with intermittent mixing.  
     [0273] For preparation of saponified standards, each standard stock is mixed with 3 milliliters of 0.3N KOH/MEOH and 25 microliters of 5-alpha Cholestane. The standards are capped, heated for one hour at 70 degrees C. and extracted. Standard 1 will include a combination of 40 microliters of 20 mg/ml Stocks of each of stigmasterol, coprostanol and beta-sitosterol. Standard 2 will be a combination of one microliter of 20 mg/ml cholesterol (0.04 ug/ul) and 5 microliters of 20 mg/ml sitostanol (0.2 ug/ul). Standard 3 will be a combination of 40 microliters of 20 mg/ml cholesterol (1.6 ug/ul) and 200 microliters of 20 mg/ml sitostanol (8.0 ug/ul).  
     [0274] For preparation of non-saponified standards, the standards are pipetted into one milliliter V-vials and 25 microliters of 5-alpha cholestane is added. The standards are evaporated to dryness in the Reacti-Therm heating block, removed from the block and allowed to cool. Methylene chloride (500 ul) is added. The extracts are mixed and filtered through the Whatman Anatop filters. Standard 1 will include the combination of 40 microliters of 20 mg/ml stocks of each stigmasterol, coprostanol and beta-sitosterol. Standard 2 will include the combination of 5 microliters of 20 mg/ml cholesterol (0.2 ug/ul) and 25 microliters of 20 mg/ml of sitostanol (1.0 ug/ul). Standard 3 will include the combination of 20 microliters of 20 mg/ml cholesterol (0.8 ug/ul) and 100 microliters of 20 mg/ml sitostanol (4.0 ug/ul). Standard 4 will include the combination of 80 microliters of 20 mg/ml cholesterol (3.2 ug/ul) and 300 microliters of 20 mg/ml sitostanol (12.0 ug/ul).  
     [0275] All tubes are removed from the heating blocks and cooled. Each saponified sample and standard is filtered through a Whatman Autovial Syingeless Filter Device, 0.45 um, PTFE (Teflon) membrane. Each tube is washed with 10 mL of petroleum ether, vortexed and combined in the filtering device. The plunger is pushed to collect the sample in a clean 50 mL glass tube. Additional petroleum ether (10 mL) is added to the sample in the 50 mL tube along with 2 mL of water. Each sample is vortexed at a moderate speed (mixing too fast will cause emulsions to form) for 20 seconds. After the layers separated, 2×7 mL of the petroleum ether phase is removed and transfered to 16×125 millimeter glass tubes. The samples are extracted one more time with the addition of 10 mL of petroleum ether and 8 mL are removed, combining the extracts of each sample. All tubes are evaporated to dryness under a stream of nitrogen gas at 70° C. The residue of each sample is quantitatively transferred to 1.5 mL glass conical vials using 3×0.5 mL washes of petroleum ether. The samples are once again evaporated to dryness. After the vials cool to room temperature, 500 microliters of methylene chloride are added. All samples and standards are filtered through Whatman Anotop 10 Plus (0.2 um, 10 mm) syringe filters. Sufficient filtrate (approximately 300 microliters) is collected into footed micro GC sample tubes. The footed micro tubes are placed in screw capped vials and tightened firmly. Analysis will be by the Hewlett Packard GC procedure.  
     [0276] CETP Activity Assay in Human Plasma (Tritiated Cholesteryl Ester)  
     [0277] Blood is to be obtained from healthy volunteers. Blood is collected in tubes containing EDTA (EDTA plasma pool). The EDTA human plasma pool previously stored at −20° C., is to be thawed at room temperature, and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([ 3 H]CE-HDL) as described by Morton and Zilversmit ( J. Biol. Chem.,  256, 11992-95 (1981)), is to be added to the plasma to a final concentration of (25 μg/ml cholesterol). Inhibitor compounds are to be added to the plasma as follows: Equal volumes of the plasma containing the [ 3 H]CE-HDL (396 μl) are added by pipette into micro tubes (Titertube®, Bio-Rad laboratories, Hercules, Calif.). Compounds, usually dissolved as 20-50 mM stock solutions in DMSO, are to be serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanol). Four μl of each of the serial dilutions of inhibitor compounds or DMSO alone are then added to each of the plasma tubes. The tubes are immediately mixed. Triplicate aliquots (100 μl) from each plasma tube are then transferred to wells of 96-well round-bottomed polystyrene microtiter plates (Corning, Corning, N.Y.). Plates are sealed with plastic film and incubated at 37° C. for 4 hours. Test wells are to contain plasma with dilutions of inhibitor compounds. Control wells are to contain plasma with DMSO alone. Blank wells are to contain plasma with DMSO alone that are left in the micro tubes at 4° C. for the 4 hour incubation and are added to the microtiter wells at the end of the incubation period. VLDL and LDL are precipitated by the addition of 10 μl of precipitating reagent (1% (w/v) dextran sulfate (Dextralip50)/0.5 M magnesium chloride, pH 7.4) to all wells. The wells are mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates are then centrifuged at 1000×g for 30 min at 10° C. The supernatants (50 μl) from each well are then transferred to Picoplate™ 96 plate wells (Packard, Meriden, Conn.) containing 250:1 Microscint™-40 (Packard, Meriden, Conn.) The plates are heat-sealed (TopSeal™-P, Packard, Meriden, Conn.) according to the manufacturer&#39;s directions and mixed for 30 min. Radioactivity will be measured on a microplate scintillation counter (TopCount, Packard, Meriden, Conn.). IC 50  values will be determined as the concentration of inhibitor compound inhibiting transfer of [ 3 H]CE from the supernatant [ 3 H]CE-HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells. The maximum percentage transfer (in the control wells) will be determined using the following equation:  
         %                 Transfer     =         [       dpm   blank     -     dpm   control       ]     ×   100       dpm   blank                     
 
     [0278] The percentage of control transfer determined in the wells containing inhibitor compounds is determined as follows:  
         %                 Control     =         [       dpm   blank     -     dpm   test       ]     ×   100         dpm   blank     -     dpm   control                       
 
     [0279] IC 50  values will be calculated from plots of % control versus concentration of inhibitor compound.  
     [0280] CETP Activity In Vitro  
     [0281] The ability of compounds to inhibit CETP activity are assessed using an in vitro assay that measures the rate of transfer of radiolabeled cholesteryl ester ([ 3 H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn et al. (Glenn and Melton, “Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein,”  Meth. Enzymol.,  263, 339-351 (1996)). CETP can be obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP (Wang, S. et al.  J. Biol. Chem.  267, 17487-17490 (1992)). To measure CETP activity, [ 3 H]CE-labeled HDL, LDL, CETP and assay buffer (50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine-tetraacetic acid; 1% bovine serum albumin) are incubated in a volume of 200 μl, for 2 hours at 37° C. in 96 well plates. LDL is differentially precipitated by the addition of 50 μl of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. The solution (200 μl) is transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL is measured by liquid scintillation counting. Correction for non-specific transfer or precipitation is made by including samples that do not contain CETP. The rate of [ 3 H]CE transfer using this assay is linear with respect to time and CETP concentration, up to 25-30% of [ 3 H]CE transferred.  
     [0282] The potency of test compounds can be determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of [ 3 H]CE from HDL to LDL. This value is defined as the IC 50 . The ICSO values determined from this assay will be accurate when the IC 50  is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC 50  may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (&lt;50 nM)  
     [0283] Inhibition of CETP Activity In Vivo  
     [0284] Inhibition of CETP activity by a test compound can be determined by administering the compound to an animal by intravenous injection or oral gavage, measuring the amount of transfer of tritium-labeled cholesteryl ester ([ 3 H]CE) from HDL to VLDL and LDL particles, and comparing this amount of transfer with the amount of transfer observed in control animals.  
     [0285] Male golden Syrian hamsters are to be maintained on a diet of chow containing 0.24% cholesterol for at least two weeks prior to the study. For animals receiving intravenous dosing, immediately before the experiment, animals are anesthetized with pentobarbital. Anesthesia is maintained throughout the experiment. In-dwelling catheters are to be inserted into the jugular vein and carotid artery. At the start of the experiment all animals will receive 0.2 ml of a solution containing [ 3 H]CE-HDL into the jugular vein. [ 3 H]CE-HDL is a preparation of human HDL containing tritium-labeled cholesteryl ester, and is prepared according to the method of Glenn et al. ( Meth. Enzymol.,  263, 339-351 (1996)). Test compound is dissolved as a 80 mM stock solution in vehicle (2% ethanol: 98% PEG 400, Sigma Chemical Company, St. Louis, Mo., USA) and administered either by bolus injection or by continuous infusion. Two minutes after the [ 3 H]CE-HDL dose is administered, animals are to receive 0.1 ml of the test solution injected into the jugular vein. Control animals are to receive 0.1 ml of the intravenous vehicle solution without test compound. After 5 minutes, the first blood samples (0.5 ml) are taken from the carotid artery and collected in standard microtainer tubes containing ethylenediamine tetraacetic acid. Saline (0.5 ml) is injected to flush the catheter and replace blood volume. Subsequent blood samples are to be taken at two hours and four hours by the same method. Blood samples are mixed well and kept on ice until the completion of the experiment. Plasma is obtained by centrifugation of the blood samples at 4° C. The plasma (50 μl) is treated with 5 μl of precipitating reagent (dextran sulfate, 10 g/l; 0.5 M magnesium chloride) to remove VLDL/LDL. After centrifugation, the resulting supernatant (25 μl) containing the HDL will be analyzed for radioactivity using a liquid scintillation counter.  
     [0286] The percentage [ 3 H]CE transferred from HDL to LDL and VLDL (% transfer) will be calculated based on the total radioactivity in equivalent plasma samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals will be 20% to 35% after 4 hours.  
     [0287] Alternatively, conscious, non-anesthetized animals can receive an oral gavage dose of test compound as a suspension in 0.1% methyl cellulose in water. At a time determined for each compound at which plasma levels of the test substance reach their peak (C max ) after oral dosing, the animals are to be anesthetized wish pentobarbital and then dosed with 0.2 ml of a solution containing [ 3 H]CE-HDL into the jugular vein as described above. Control animals are to receive 0.25 ml of the vehicle solution without test compound by oral gavage. After 4 hours, the animals are to be sacrificed, blood samples are collected, and the percentage [ 3 H]CE transferred from HDL to LDL and VLDL (% transfer) is assayed as described above.  
     [0288] Alternatively, inhibition of CETP activity by a test compound can be determined by administering the compound to mice that have been selected for expression of human CETP (hCETP) by transgenic manipulation (hCETP mice) Test compounds can be administered by intravenous injection, or oral gavage and the amount of transfer of tritium-labeled cholesteryl ester ([ 3 H]CE) from HDL to VLDL and LDL particles is determined, and compared to the amount of transfer observed in control animals. C57Bl/6 mice that are homozygous for the hCETP gene are to be maintained on a high fat chow diet, such as TD 88051, as described by Nishina et al. ( J Lipid Res.,  31, 859-869 (1990)) for at least two weeks prior to the study. Mice are to receive an oral gavage dose of test compound as a suspension in 0.1% methyl cellulose in water or an intravenous bolus injection of test compound in 10% ethanol and 90% polyethylene glycol. Control animals are to receive the vehicle solution without test compound by oral gavage or by an intravenous bolus injection. At the start of the experiment all animals will receive 0.05 ml of a solution containing [ 3 H]CE-HDL into the tail vein. [ 3 H]CE-HDL will be a preparation of human HDL containing tritium-labeled cholesteryl ester, and is prepared according to the method of Glenn et al. ( Meth. Enzymol.,  263, 339-351 (1996)). After 30 minutes, the animals are exsanguinated and blood collected in standard microtainer tubes containing ethylenediamine tetraacetic acid. Blood samples are mixed well and kept on ice until the completion of the experiment. Plasma will be obtained by centrifugation of the blood samples at 4° C. The plasma is separated and analyzed by gel filtration chromatography and the relative proportion of [ 3 H]CE in the VLDL, LDL and HDL regions will be determined.  
     [0289] The percentage [ 3 H]CE transferred from HDL to LDL and VLDL (% transfer) will be calculated based on the total radioactivity in equivalent plasma samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals will be 20% to 35% after 30 min.  
     [0290] Intestinal Cholesterol Absorption Assay  
     [0291] A variety of compounds are shown to inhibit cholesterol absorption from the intestinal tract. These compounds lower serum cholesterol levels by reducing intestinal absorption of cholesterol from both exogenous sources (dietary cholesterol) and endogenous cholesterol (secreted by the gall bladder into the intestinal tract).  
     [0292] In hamsters the use of a dual-isotope plasma ratio method to measure intestinal cholesterol absorption has been refined and evaluated as described by Turley et al. (J. Lipid Res. 35, 329-339 (1994), herein incorporated by reference).  
     [0293] Male hamsters weighing 80-100 g are to be given food and water ad libitum in a room with 12 hour alternating periods of light and dark. Four hours into the light period, each hamster is administered first an intravenous dose of 2.5 μCi of [1,2- 3 H]cholesterol suspended in Intralipid (20%) and then an oral dose of [4- 14 C]cholesterol in an oil of medium chain triglycerides (MCT). The i.v. dose is given by injecting a 0.4 ml volume of the Intralipid mixture into the distal femoral vein. The oral dose is given by gavaging a 0.6 ml volume of the MCT oil mixture introduced intragastrically via a polyethylene tube. After 72 hours the hamsters are bled and the amount of  3 H and  14 C in the plasma and in the original amount of label administered are determined by liquid scintillation spectrometry. The cholesterol absorption will be calculated based on the following equation:  
     [0294] Percent cholesterol absorbed= 
           %  of  oral  dose  per  ml  of  72  hour  plasma  sample       %  of  i.v.  dose  per  ml  of  72  hour  plasma  sample       ×   100                 
 
     [0295] Microsomal Triglyceride Transfer Protein (MTP) Assay  
     [0296] MTP can be purified from liver tissue or cultured cells (e.g. HepG2 cells) using standard methods as described by Ohringer et al. (Acta Crystallogr. D52, 224-225 (1996), herein incorporated by reference).  
     [0297] Subsequent analysis of MTP activity can be performed as described by Jamil et al. (Proc. Natl. Acad. Sci. 93, 11991-11995 (1996), herein incorporated by reference).  
     [0298] The basis of this assay is to measure the transfer of labeled triglycerides from a population of donor vesicles to a population of acceptor vesicles in the presence of MTP. Inhibitors of MTP can be evaluated by adding them to the mixture prior to the introduction of MTP. Donor vesicles are prepared by sonication of an aqueous mixture of egg phospholipids, cardiolipin,  3 H-labeled phospholipid and  14 C-labeled triglycerides. Acceptor vesicles are prepared by sonication of an aqueous mixture of egg phospholipids. The vesicle solutions are mixed together, with or without added MTP inhibitors, and MTP is added to initiate the transfer reaction. The assay is terminated after 60 minutes by addition of 0.5 ml of DE-52 cellulose followed by centrifugation to pellet the donor molecules. The amount of  3 H and  14 C in the pellet and in the original amount of label in the mixture are determined by liquid scintillation spectrometry. The lipid transfer rate will be calculated based on first order kinetics using the expression: 
     
       [S]=[S] 
       0 
       e 
       −kt 
     
     [0299] where [S] 0  and [S] are the fractions of  14 C label in the donor membrane pellet at times 0 and t, respectively, and the term k is the fraction of label transferred per unit time.  
     [0300] Plasma Lipids Assay in Rabbits  
     [0301] Plasma lipids can be assayed using standard methods as reported by J. R. Schuh et al.,  J. Clin. Invest.,  91, 1453-1458 (1993), herein incorporated by reference. Groups of male, New Zealand white rabbits are placed on a standard diet (100 g/day) supplemented with 0.3% cholesterol and 2% corn oil (Zeigler Bothers, Inc., Gardners, Pa.). Water is available ad lib. Groups of control and treated animals are killed after 1 and 3 months of treatment. Tissues are removed for characterization of atherosclerotic lesions. Blood samples are to be taken for determination of plasma lipid concentrations.  
     [0302] Plasma Lipids  
     [0303] Plasma for lipid analysis is to be obtained by withdrawing blood from the ear vein into EDTA-containing tubes (Vacutainer; Becton Dickenson &amp; Co., Rutherford, N.J.), followed by centrifugal separation of the cells. Total cholesterol will be determined enzymatically, using the cholesterol oxidase reaction (C. A. Allain et al.,  Clin. Chem.,  20, 470-475 (1974), herein incorporated by reference). HDL cholesterol will also be measured enzymatically, after selective precipitation of LDL and VLDL by dextran sulfate with magnesium (G. R. Warnick et al.,  Clin. Chem.,  28, 1379-1388 (1982), herein incorporated by reference). Plasma triglyceride levels will be determined by measuring the amount of glycerol released by lipoprotein lipase through an enzyme-linked assay (G. Bucolo et al.,  Clin. Chem.,  19, 476-482 (1973), herein incorporated by reference).  
     [0304] Atherosclerosis  
     [0305] Animals are to be killed by pentobarbital injection. Thoracic aortas are rapidly removed, immersion fixed in 10% neutral buffered formalin, and stained with oil red O (0.3%). After a single longitudinal incision along the wall opposite the arterial ostia, the vessels are pinned open for evaluation of the plaque area. The percent plaque coverage is determined from the values for the total area examined and the stained area, by threshold analysis using a true color image analyzer (Videometric 150; American Innovision, Incl, San Diego, Calif.) interfaced to a color camera (Toshiba 3CCD) mounted on a dissecting microscope. Tissue cholesterol will be measured enzymatically as described, after extraction with a chloroform/methanol mixture (2:1) according to the method of Folch et al. (J. Biol. Chem., 226, 497-509 (1957), herein incorporated by reference).  
     [0306] In Vitro Vascular Response  
     [0307] The abdominal aortas are rapidly excised, after injection of sodium pentobarbital, and placed in oxygenated Krebs-bicarbonate buffer. After removal of perivascular tissue, 3-mm ring segments are cut, placed in a 37° C. muscle bath containing Krebs-bicarbonate solution, and suspended between two stainless steel wires, one of which is attached to a force transducer (Grass Instrument Co., Quincy, Mass.). Force changes in response to angiotensin II added to the bath will be recorded on a chart recorder.  
     [0308] Renal Hypertensive Rat Model  
     [0309] A combination therapy of an antihypertensive agent and an ileal bile acid transport inhibitor may be evaluated for blood pressure lowering activity in the renal-artery ligated hypertensive rat, a model of high renin hypertension. In this model, six days after litigation of the left renal artery, both plasma renin activity and blood pressure are elevated significantly (J. L. Cangiano et al,  J. Pharmacol. Exp. Ther.,  206, 310-313 (1979)). Male Sprague-Dawley rats are instrumented with a radiotelemetry blood pressure transmitter for continuous monitoring of blood pressure. The rats are anesthetized with a mixture of ketamine-HCl (100 mg/kg) and acepromazine maleate (2.2 mg/kg). The abdominal aorta is exposed via a midline incision. Microvascular clamps are placed on the aorta distal to the renal arteries and the iliac bifurcation. The aorta is punctured with a 22-gauge needle and the tip of a catheter is introduced. The catheter, which is held in place by a ligature in the psoas muscle, is connected to a radiotelemetry blood pressure transmitter (Mini-Mitter Co., Inc., Sunriver, Oreg.). The transmitter is placed in the peritoneal cavity and sutured to abdominal muscle upon closing of the incision. Rats are housed singly above a radiotelemetry receiver and are allowed standard rat cho and water ad libitum. At least five days are allowed for recovery from surgery. Mean arterial pressure and heart rate are measured on a data recorder as is appropriate, such as a mini-computer. Data Data are sampled for 10 seconds at 200-500 Hz at 2.5 to 10 min intervals 24 hours per day. After collecting control data for 24 hours, the rats are anesthetized with methohexital (30 mg/kg, i.p.) and supplemented as needed. A midline abdominal incision is made, approximately 2 cm in length to expose the left kidney. The renal artery is separated from the vein near the aorta, with care taken not to tramatize the vein. The artery is completely ligated with sterile 4-O silk. The incision is closed by careful suturing of the muscle layer and skin. Six days later, when MAP is typically elevated by 50-70 mmHg, an antihypertensive agent or a combination with one or more cardiovascular therapeutic agents are administered by gavage each day for about 8 weeks. Single drug dosing is carried out using 20 and 200 mg/kg/day of the antihypertensive agent (for example, eplerenone) and 1, 3, 10, 30, and 100 mg/kg/day of the other cardiovascular therapeutic agent. Drug mixtures are obtained by administering a combination of a dose of 1, 3, 10, 30, or 100 mg/kg/day of the other cardiovascular therapeutic agent with a dose of either 20 or 200 mg/kg/day of the antihypertensive agent. Blood pressure lowering is monitored by the radiotelemetry system and responses with the compounds are compared to a response obtained in vehicle-treated animals. Plasma and urinary sodium and potassium levels are monitored as a measure of the effectiveness of the aldosterone blockade. Urine samples are collected overnight using metabolic cages to isolate the samples. Plasma samples are obtained by venous catheterization. Sodium and potassium are measured by flame photometry. Cardio fibrosis is determined by histological and chemical measurements of the excised hearts following perfusion fixation. Left and right ventricles are weighed, embedded, and sectioned. Subsequently, sections are stained with picrosirius red and the red staining collagen areas are quantitated by computerized image analysis. The apex of th heart is acid digested and the free hydroxyproline measured calorimetrically. It is expected that MAP will be significantly lowered toward normal pressures in the test animals, treated with the combination therapy and that the condition of myocardial fibrosis will be arrested or avoided.  
     [0310] Effect of an IBAT Inhibitor and an Antihypertensive Agent, Alone and in Combination, on the Treatment of Atherosclerosis  
     [0311] This study will be a prospective randomized evaluation of the effect of a combination of an IBAT inhibitor or a pharmaceutically acceptable salt thereof and an antihypertensive agent on the progression/regression of coronary and carotid artery disease. The study is used to show that a combination of an IBAT inhibitor or a pharmaceutically acceptable soft thereof and an antihypertensive agent 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.  
     [0312] This study will be an angiographic documentation of coronary artery diseasecarried 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 will be admitted into the study after satisfying certain entry criteria set forth below.  
     [0313] Entry criteria: Subjects accepted for entry into this trial must satisfy certain criteria. Thus the subject must be an adult, either male or female, aged 18-80 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. It is also required that the segments to be analyzed have not suffered a thrombotic event, such as a myocardial infarct (MI). Thus the requirement for non-MI vessels. 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 40% determined by catheterization or radionuclide ventriculography or ECHO cardiogram at the time of the qualifying angiogram or within the previous three months of the acceptance of the qualifying angiogram provided no intervening event such as a thrombotic event or procedure such as PTCA has occurred.  
     [0314] Generally, due to the number of patients and the physical limitations of any one facility, the study will be carried out at multiple sites. At entry into the study, subjects undergo quantitative coronary angiography as well as B-mode carotid artery ultrasonography and assessment of carotid arterial compliance at designated testing centers. This will establish baselines for each subject. Once admitted into the test, subjects are randomized to receive an antihypertensive agent (for example, eplerenone) or a pharmaceutically acceptable salt thereof (the dose is dependent upon the particular antihypertensive agent or salt thereof chosen) and placebo or antihyperlipidemic agent such as an IBAT inhibitor (50 mgs) and placebo or an antihypertensive agent or a pharmaceutically acceptable salt thereof (the dose is dependent upon the particular antihypertensive agent or salt thereof chosen) and IBAT inhibitor (50 mgs). It will be recognized by a skilled person that the free base form or other salt forms of antihypertensive agent or the free base form or other salt forms of the IBAT inhibitor may be used in this invention. Calculation of the dosage amount for these other forms of the IBAT inhibitor and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The amount of the antihypertensive agent may be varied as required. The amount of the IBAT inhibitor will be titrated down from 80 mg if it is determined by the physician to be in the best interests of the subject. The subjects are monitored for a one to three year period, generally three years being preferred. B-mode carotid ultrasound assessment of carotid artery atherosclerosis and compliance are performed at regular intervals throughout the study. Generally, six 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 one to three year treatment period. The baseline and post-treatment 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.  
     [0315] The primary objective of this study is to show that the combination of an antihypertensive agent and an IBAT inhibitor 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.  
     [0316] The primary endpoint of the study is the change in the average mean segment diameter of the coronary artery tree. Thus, 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. After the average segment diameter of many segments has been determined, the average of all segment averages is determined to arrive at the average mean segment diameter. The mean segment diameter of subjects taking the IBAT inhibitor or a pharmaceutically acceptable salt thereof and the antihypertensive agent or a pharmaceutically acceptable acid addition salt thereof will decline more slowly, will be halted completely, or there will be an increase in the mean segment diameter. These results will represent slowed progression of atherosclerosis, halted progression of atherosclerosis and regression of atherosclerosis, respectively.  
     [0317] The secondary objective of this study is that the combination of an antihypertensive agent and the IBAT inhibitor or a pharmaceutically acceptable salt thereof 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 amlodipine or a pharmaceutically acceptable acid addition salt thereof or IBAT inhibitor or a pharmaceutically acceptable salt thereof alone. The intimal-medial thickness of subjects taking an IBAT inhibitor or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable acid addition salt thereof will increase more slowly, will cease to increase or will decrease. These results represent slowed progression of atherosclerosis, hafted progression of atherosclerosis and regression of atherosclerosis, respectively. Further, these results may be used to facilitate dosage determinations.  
     [0318] The utility of the compounds of the present invention as medical agents in the treatment of angina pectoris in mammals (e.g., humans) Is demonstrated by the activity of the compounds of this invention in conventional assays and the clinical protocol described below:  
     [0319] Effect of IBAT Inhibitor and an Antihypertensive Agent, Alone and in Combination, on the Treatment of Angina  
     [0320] This study will be a double blind, parallel arm, randomized study to show the effectiveness of an IBAT inhibitor or a pharmaceutically acceptable salt thereof and an antihypertensive agent given in combination in the treatment of symptomatic angina.  
     [0321] Entry criteria: 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 30-50% is considered to be significant  
     [0322] Each subject is evaluated for about ten to thirty-two weeks. At least ten 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 subject are evaluated to complete the study. Subjects are screened for compliance with the entry criteria, set forth below, during a four week run in phase. After the screening criteria are met, subjects are washed out from their current ant-anginal medication and stabilized on a long acting nitrate such as nitroglycerine, isosorbide-5-mononitrate or isosorbide dinitrate. The term “washed out”, when used in connection with this screen, means the withdrawal of current anti-anginal medication so that substantially all of the medication is eliminated from the body of the subject A period of eight weeks is preferably allowed for both the wash out period and for the establishment of the subject on stable doses of the 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 wash out phase. After subjects are stabilized on nitrates, the subjects enter the randomization phase provided the subjects continue to have either one or two angina attacks per week. In the randomization phase, the subjects are randomly placed into one of the four arms of the study set forth below. After completing the wash out phase, subjects in compliance with the entry criteria undergo twenty four hour ambulatory electrocardigram (ECG) such as Holter monitoring, exercise stress testing such as a treadmill and evaluation of myocardial perfusion using PET (photon emission tomography) scanning to establish a baseline for each subject. When conducting a stress test, 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.  
     [0323] After the baseline investigations have been completed, subjects are initiated on one of the following four arms of the study: (1) placebo; (2) IBAT inhibitor (about 1 mg to about 80 mg); (3) an antihypertensive agent (dose is dependent upon the particular antihypertensive agent chosen); or (4) a combination of the above doses of IBAT inhibitor and antihypertensive agent together. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the IBAT inhibitor may be used in this invention. Calculation of the dosage amount for these other forms of the IBAT inhibitor and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The subjects are then monitored for two to twenty four weeks.  
     [0324] After the monitoring period has ended subjects will undergo the following investigations: (1) twenty four hour ambulatory ECG, such as Holler monitoring, (2) exercise stress testing (e.g. treadmill using the modified Bruce Protocol); and (3) evaluation of myocardial perfusion using PET scanning. Patents keep a diary of painful ischemic events and nitroglycerine consumption. It is generally desirable to have an accurate record of the number of anginal attacks suffered by the patent during the duration of the test Since a patient generally takes nitroglycerin to ease the pain of an anginal attack, the number of times that the patient administers nitroglycerine provides a reasonably accurate record of the number of anginal attacks.  
     [0325] To demonstrate the effectiveness and dosage of the drug combination of this invention, 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 an ultrasound.  
     [0326] 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,  
     [0327] Effect of an IBAT Inhibitor and an Antihypertensive Agent, Alone and in Combination, on the Treatment of Subjects Having Both Hypertension and Hyperlipidemia  
     [0328] This study will be a double blind, parallel arm, randomized study to show the effectiveness of an IBAT inhibitor or a pharmaceutically acceptable salt thereof and an antihypertensive agent given in combination in controlling both hypertension and hyperlipidemia in subjects who have mild, moderate, or severe hypertension and hyperlipidiemia  
     [0329] 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.  
     [0330] Entry criteria: 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 low density lipoprotein (LDL) 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 greater than or equal to 190. 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 greater than or equal to 160. If the subject has CHID, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 130.  
     [0331] Positive risk factors include (1) male over 45, (2) female over 55 wherein the female is not undergoing hormone replacement therapy (HIRT), (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, and (7) the subject has hypertension. An HDL of greater than 60 is considered a negative risk factor and will offset one of the above mentioned positive risk factors. The presence of hypertension is evidenced by a sitting diastolic blood pressure (BP) of greater than 90 or sitting systolic BP of greater than 140. All blood pressures are generally determined as the average of three measurements taken five minutes apart. 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 if Step 1 diet The NCEP ATP 11 (adult treatment panel, 2nd revision) Step I 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 the 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 I diet. After the four week wash out 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 twelve hours, at which time lipid levels are measured. After the baseline investigations are performed subjects are started on one of the following: (1) a fixed dose of an antihypertensive agent, dose dependent upon the particular antihypertensive agent chosen; (2) a fixed dose of an IBAT inhibitor, generally about 1 to 80 mg; or (3) a combination of the above doses of the IBAT inhibitor and the antihypertensive agent together. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the IBAT inhibitor may be used in this invention. Calculation of the dosage amount for these other forms of the IBAT inhibitor and amlodipine besylate 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 six weeks, and generally for no more than eight weeks. The subjects return to the testing center at the conclusion of the six to eight 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, VLDL (very low density lipoprotein) 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. The utility of the compounds of the present invention as medical agents in the management of cardiac risk in mammals (e.g., humans) at risk for an adverse cardiac event is demonstrated by the activity of the compounds of this invention in conventional assays and the clinical protocol described below.  
     [0332] Effects of an IBAT Inhibitor and an Antihypertensive Agent, Alone and in Combination, on Subjects at Risk of Future Cardiovascular Events  
     [0333] This study will be a double blind, parallel arm, randomized study to show the effectiveness of an IBAT inhibitor or a pharmaceutically acceptable salt thereof and an antihypertensive agent 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 the IBAT inhibitor or a pharmaceutically acceptable salt thereof and the antihypertensive agent in controlling cardiovascular risk by controlling both hypertension and hyperlipidemia in patients who have both mild to moderate hypertension and hyperlipidemia.  
     [0334] Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are recruited to ensure that about 400 to 800 subjects are evaluated to complete the study.  
     [0335] Entry criteria: Subjects included in the study are male or female adult subjects between 18 and 80 years of age with a baseline five year risk which risk is above the median for the subject&#39;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 high density lipoprotein (HDL) of more than one standard deviation above the norm for the Framingham Population are all evaluated in determining whether a patent 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. After all screening criteria are met, patients are washed out from their current antihypertensive and lipid lowering medication and any other medication which will impact the results of the screen. The patients are then placed on the NCEP ATP 11 Step I diet, as described above. Newly diagnosed subjects generally remain untreated until the test begins—These subjects are also placed on the NCEP ATP 11 Step 1 diet. After the four week wash out and diet stabilization period, subjects undergo the following baseline investigations: (1) blood pressure; (2) fasting; (3) DPW 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.  
     [0336] After the baseline investigations are performed patents will be started on one of the following: (1) a fixed dose of an antihypertensive agent, dose dependent upon the particular antihypertensive agent chosen; (2) a fixed dose of an IBAT inhibitor (about 1 to 80 mg); or (3) the combination of the above doses of the IBAT inhibitor and an antihypertensive agent. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the IBAT inhibitor may be used in this invention. Calculation of the dosage amount for these other forms of the IBAT inhibitor and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. Patients are kept on these doses and are asked to return in six to eight weeks so that the baseline evaluations can be repeated. At this time 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  
     [0337] The above assays demonstrating the effectiveness of amlodipine or pharmaceutically acceptable acid addition salts thereof and an IBAT inhibitor or pharmaceutically acceptable salts thereof in the treatment of angina pectoris, atherosclerosis, hypertension and hyperlipidemia together, and the management of cardiac risk, also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases. The following 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 kg. The skilled practitioner will readily be able to determine the dosage amount required for a subject whose weight falls outside the 65 kg 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.  
     [0338] By way of general example, in accordance with this invention, the below-listed antihypertensive agent may be administered in the following daily dosage amounts:  
     [0339] diltiazem, generally about 120 mg to about 480 mg;  
     [0340] verapamil, generally about 20 mg to about 48 mg;  
     [0341] felodipine, generally about 2.5 mg to about 40 mg;  
     [0342] isradipine, generally about 2.5 mg to about 40 mg;  
     [0343] lacidipine, generally about 1 mg to about 6 mg;  
     [0344] nicardipine, generally about 32 mg to about 120 mg;  
     [0345] nifedipine, generally about 10 mg to about 120 mg;  
     [0346] nimodipine, generally about 120 mg to about 480 mg;  
     [0347] nisoldipine, generally about 5 mg to about 80 mg;  
     [0348] nitrendipine, generally about 5 mg to about 20 mg;  
     [0349] benazepril, generally about 10 mg to about 80 mg;  
     [0350] captopril, generally about 50 mg to about 150 mg;  
     [0351] enalapril, generally about 5 mg to about 40 mg;  
     [0352] fosinopril, generally about 10 mg to about 80 mg;  
     [0353] lisinopril, generally about 10 mg to about 80 mg;  
     [0354] quinapril, generally about 10 mg to about 80 mg;  
     [0355] losartan, generally about 25 mg to about 100 mg;  
     [0356] valsartan, generally about 40 mg to about 640 mg;  
     [0357] doxazosin, generally about 0.5 mg to about 16 mg;  
     [0358] prazosin, generally about 1 mg to about 40 mg;  
     [0359] trimazosin, generally about 1 mg to about 20 mg;  
     [0360] arniloride, generally about 5 mg to about 20 mg; and  
     [0361] eplerenone, generally about 10 to about 150 mg.  
     [0362] It will be recognized by those skilled in the art that dosages for the above antihypertensive compounds must be individualized to each specific subject. This individualization will depend upon the medical history of the subject and whether the subject is concurrently taking other medications which may or may not interfere or have an adverse effect in combination with the above antihypertensives. Individualization is then achieved by beginning with a low dose of the compound and titrating the amount up until the desired therapeutic effect is achieved. In general, in accordance with this invention, the IBAT inhibitor is generally administered in a dosage of about 0.1 mg/day to about 500 mg/day. Preferably, the IBAT inhibitor is administered in a dosage of about 1 mg/day to about 100 mg/day.  
     [0363] Since the present invention relates to the treatment of diseases and conditions with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit includes two separate pharmaceutical compositions: an antihypertensive agent or a pharmaceutically acceptable salt thereof and an IBAT inhibitor 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. Typically 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.  
     [0364] The examples herein can be performed by substituting the generically or specifically described therapeutic compounds or inert ingredients for those used in the preceding examples.  
     [0365] The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.