(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`Bll
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`25 September 2008 (25.09.2008)
`
`PCT
`
`(10) International Publication Number
`WO 2008/115574 Al
`(74) Agents: CONNELL, Michaele et al.; Arent Fox LLP,
`1050 Connecticut Avenue N.W., Washington, DC 20036
`(US).
`
`(81) Designated States (unless othe1Wise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, l'v1K, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA,ZM,ZW.
`
`(84) Designated States (unless othe1Wise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`
`(51) International Patent Classification:
`AOJN 43100 (2006.01)
`AOJN 43178 (2006.01)
`
`(21) International Application Number:
`PCT/US2008/003728
`
`(22) International Filing Date: 21 March 2008 (21.03.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/907,102
`
`21March2007 (21.03.2007) US
`
`(71) Applicant (for all designated States except US): RE(cid:173)
`LIANT PHARMACEUTICALS, INC. [-/US]; 110
`Allen Road, Liberty Corner, NJ 07938 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BOBOTAS, George
`[US/US]; Clo Reliant Pharmaceuticals, Inc., 110 Allen
`Road, Liberty Corner, NJ 07938 (US). RONGEN, Roelof,
`M.L [US/US]; Clo Reliant Pharmaceuticals, Inc., 110
`Allen Road, Liberty Corner, NJ 07938 (US). FAWZY,
`Abdel [US/US]; Clo Reliant Pharmaceuticals, Inc., 110
`Allen Road, Liberty Corner, NJ 07938 (US). KLING,
`Douglas [US/US]; Clo Reliant Pharmaceuticals, Inc., 110
`Allen Road, Liberty Corner, NJ 07938 (US).
`
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`r-.... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`~
`If) (54) Title: CB 1 ANTAGONIST AND A DYSLIPIDEMIC AGENT AND/OR METABOLIC REGULATOR, AND METHODS
`~ OF MAKING AND USING SAME
`?"""I Qo (57) Abstract: The present invention relates to a CB 1 antagonist and a dyslipidemic agent and/or a metabolic regulator. The present
`O
`0
`M
`O cardiovascular and vascular events; reducing insulin resistance, fasting glucose levels and postprandial glucose levels; treating and/or
`
`invention further includes methods of using formulations of a CBl antagonist and at least one of (a) omega-3 fatty acids, (b) MTP
`inhibitors, (c) DPP4 inhibitors, (d) sarsasapogenin, (e) smilagenin, (f) steroidal glycosides and/or (g) extracts of Artemisia spp. for
`treating various dyslipidemias; treating vascular disease; treating artherosclerotic disease; treating obesity; preventing or reducing
`
`:;;;..,.. preventing diabetes and/or symptoms thereof; reducing the incidence of and/or delaying the onset of metabolic syndrome; and re(cid:173)
`~ ducing the incidence of, and/or delay the onset of type II diabetes.
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`CB1 Antagonist and a Dyslipidemic Agent andlor Metabolic Regulator, and Methods of
`Making and Using Same
`
`Background of the Invention
`
`1.
`
`Field of the Invention
`
`[0001] The present invention relates, generally, to compositions comprising a
`
`cannabinoid 1 (CB1) antagonist and a dyslipidemic agent and/or a metabolic regulator.
`Presently preferred dyslipidemic agents used in the compositions of the present
`
`invention may include, but are not limited to, omega-3 fatty acids, peroxisome
`
`proliferator-activated receptor (PPAR) agonists/antagonists, microsomal triglyceride
`
`transfer protein (MTP) inhibitors, and/or dipeptidyl peptidase-4 (DPP4) inhibitors.
`
`Presently preferred metabolic regulators used in the compositions of the present
`
`invention may include, but are not limited to, sarsasapogenin, smilagenin, steroidal
`
`glycosides and extracts thereof, and extracts of Artemisia spp. The present invention
`
`also includes pharmaceutical formulations made from the compositions, and methods of
`
`making such formulations. The present invention also includes methods of using
`
`formulations of a CB1 antagonist and at least one of (a) omega-3 fatty acids, (b) MTP
`inhibitors, (c) DPP4 inhibitors, (d) sarsasapogenin, (e) smilagenin, (f) steroidal
`
`glycosides and extracts thereof, and/or (g) extracts of Artemisia spp. for treating
`
`hypertriglyceridemia, hypercholesteremia, mixed dyslipidemia, vascular disease,
`
`artherosclerotic disease, and/or obesity; preventing and/or reducing cardiovascular
`
`and/or vascular events; reducing insulin resistance, fasting glucose levels, and/or
`
`postprandial glucose levels; and preventing and/or reducing the incidence of and/or
`delaying the onset of metabolic syndrome. The present invention further includes
`
`methods of using formulations of a CB1 antagonist and at least one of (a) omega-3 fatty
`
`acids, (b) MTP inhibitors, (c) DPP4 inhibitors, (d) PPAR agonists/antagonists, (e)
`
`sarsasapogenin, (f) smilagenin, (g) steroidal glycosides and extracts thereof, and/or (h)
`
`extracts of Artemisia spp. for preventing, reducing the incidence of, and/or delaying the
`
`onset of type II diabetes.
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`Description of the Related Art
`2.
`[0002] Dyslipidemia is a general term used to describe various disorders of lipoprotein
`metabolism, including lipoprotein overproduction or deficiency. Dyslipidemias may be
`
`manifested in various ways, such as by elevation of total cholesterol, elevation of "bad"
`
`low-density lipoprotein cholesterol and/or triglyceride concentrations, and reduction in
`
`"good" high-density lipoprotein cholesterol concentrations. In humans, cholesterol and
`
`triglycerides are part of lipoprotein complexes in the bloodstream, and can be separated
`via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density
`
`lipoprotein (IDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL)
`
`fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into
`
`VLDL, and released into the plasma.
`
`[0003] Dyslipidemia is often associated with diabetes and high blood pressure,
`particularly in obese/overweight patients. The relationship can also be observed in pre(cid:173)
`
`diabetic patients who exhibit "metabolic syndrome" or "Syndrome X," which is
`
`characterized by the presence of metabolic risk factors that may include 1) central
`
`obesity; 2) atherogenic dyslipidemia (blood fat disorders comprising mainly high
`triglycerides ("TG") and low HDL-cholesterol (interchangeably referred to herein as
`
`"HDL") that foster plaque buildups in artery walls); 3) raised blood pressure; 4) insulin
`resistance or glucose intolerance (the body can't properly use insulin or blood sugar); 5)
`prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood);
`and 6) a proinflammatory state (e.g., elevated high-sensitivity C-reactive protein in the
`blood). The National Cholesterol Education Program (NCEP) Adult Treatment Panel
`(ATP) Ill guidelines define metabolic syndrome by the presence of three of the following
`
`five clinical parameters: a) a waist circumference greater than 102 cm for men, and
`greater than 88 cm for women; b) a triglyceride level greater than 150 mg/di; c) an HDL(cid:173)
`
`cholesterol less than 40 mg/di for men, and less than 50 mg/di for women; d) a blood
`pressure greater than or equal to 130/85 mmHG; and e) a fasting glucose greater than
`
`110 mg/di (or fasting glucose greater than 125 mg/di, if 3 or more of the other criteria
`
`are present). Patients exhibiting the symptoms of metabolic syndrome are at increased
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`risk of coronary heart disease and other diseases related to plaque buildups in artery
`walls (e.g., stroke and peripheral vascular disease). It is estimated that over 50 million
`Americans have metabolic syndrome.
`
`[0004] The epidemics of obesity, type II diabetes, hypertension, and metabolic
`
`syndrome continue to worsen. These patients frequently do not respond to single-agent
`
`therapy, and many require combinations of drugs to address the various metabolic
`problems causing changes in their lipoprotein fractions. Although the need for
`
`combination therapy has been established in the management of hypertension and type
`
`II diabetes, it is less often used for the treatment of dyslipidemia. Most of the
`
`medications currently available for treating dyslipidemia fail to address the various
`
`additional conditions that are often associated therewith. It would therefore be desirable
`to provide compositions and methods for treating dyslipidemia, particularly in patients
`
`also suffering from obesity, type II diabetes, hypertension, and/or metabolic syndrome.
`
`There is a need in the art for compositions and methods for improving lipid profiles in
`
`patients suffering from obesity, type II diabetes, hypertension, and/or metabolic
`
`disorder.
`
`[0005] Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting
`diacylglycerol acyltransferase (DGAT) and by stimulating peroxisomal and mitochondrial
`
`beta oxidation. Marine oils, also commonly referred to as fish oils, are a good source of
`
`two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid
`
`(DHA), which have been found to regulate lipid metabolism. Omega-3 fatty acids may
`
`include, but are not limited to, omega-3 polyunsaturated, long-chain fatty acids such as
`
`a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-linolenic acid;
`
`esters of omega-3 fatty acids, optionally with glycerol, such as mono-, di- and
`
`triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary
`alcohol such as fatty acid methyl esters and fatty acid ethyl esters. Omega-3 fatty acids
`
`or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be
`
`used either in their pure form or as a component of an oil such as fish oil, preferably
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`purified fish oil concentrates. Omega-3 fatty acids have been found to have beneficial
`
`effects on the risk factors for cardiovascular diseases, especially mild hypertension,
`
`hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
`
`Omega-3 fatty acids lower serum triglycerides, increase serum HDL-cholesterol, lower
`
`systolic and diastolic blood pressure and the pulse rate, and lower the activity of the
`
`blood coagulation factor Vll-phospholipid complex. Further, omega-3 fatty acids seem
`
`to be well-tolerated, without giving rise to any severe side effects.
`
`[0006] One form of omega-3 fatty acid is a concentrate of omega-3, long chain,
`polyunsaturated fatty acids from fish oil containing DHA and EPA that is sold under the
`
`trademark LOVAZA™, which was formerly known as OMACOR®. Such a form of
`
`omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667
`
`and 5,698,594, each of which is incorporated herein by reference.
`
`[0007] Improving cholesterol and lipid levels is very important for long-term
`cardiovascular health, and is particularly important for reducing morbidity in patients
`
`who are also suffering from high blood pressure, type II diabetes, obesity, and/or
`
`metabolic syndrome. Various approaches have been taken to treat dyslipidemia.
`
`[0008] U.S. Published Application No. 2005/0281868 describes a transdermal patch for
`combination therapy with a statin and another compound, for use in treating
`
`dyslipidemia. Exemplary transdermal products include any known statin that may be
`
`transdermally administered, in combination with various drugs, including rimonabant.
`
`[0009] U.S. Published Application No. 2005/0171140 describes HMG CoA reductase
`inhibitors that may be useful for modulating blood serum lipids. These compounds may
`
`be combined with CB1 antagonists or inverse agonists, such as SR-141716 (Sanofi)
`
`and FLV-319 (Solvay).
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`[0010] U.S. Published Application No. 2005/0101542 describes a combination therapy
`for controlling appetite, including a combination of a PPAR-alpha agonist, such as
`oleoylethanolamide and oleoylethanolamide-like fatty acid alkanolamide compounds,
`and a CB1 cannabinoid receptor antagonist, such as SR-141716. Preferred PPAR(cid:173)
`
`alpha agonists are clofibrate and derivatives of clofibrate such as fenofibrate,
`bezafibrate, gemfibrozil, and ciprofibrate. The combination was described as
`synergistically reducing appetite and promoting weight loss when administered to a
`patient. The combination therapy may be used to prevent or treat diseases associated
`with obesity or overweight in mammals, and may also be useful for modulating lipid
`metabolism.
`
`[0011] U.S. Patent No. 6,875,782 describes substituted heterocyclic derivatives which
`modulate blood glucose levels, triglyceride levels, insulin levels, and non-esterified fatty
`acid levels. The compounds may be combined with various dyslipidemic agents,
`including fibrates, PPAR agonists, MTP inhibitors, CAls, statins, CETP, niacin
`derivatives, LXR, etc. (col. 37, line 6 - col. 41, line 8). The compounds may also be
`combined with anorectic agents, including cannabinoid receptor antagonists, such as
`SR-141716/rimonabant (Sanofi) or SLV-318 (Solvay).
`
`[0012] U.S. Published Application Nos. 2005/0192278, 2005/0171110, and
`
`2005/0143381 are related, and discuss azabicyclic heterocycles as cannabinoid
`receptor modulators, preferably antagonists or inverse agonists of CB1. These
`compounds may be combined with hypolipidemic agents, such as HMG CoA reductase
`inhibitors, squalene synthetase inhibitors, fibric acid derivatives, bile acid sequestrants,
`nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,
`poly(diallylmethylamine) derivatives, quaternary amine poly(diallyldimethylammonium
`chloride) and ionenes, and other serum cholesterol lowering agents. The hypolipidemic
`agent may also be an ACAT inhibitor, an upregulator of LDL receptor activity, a
`
`cholesterol absorption inhibitor, a cholesteryl transfer protein inhibitor (CETP), an ileal
`Na+/bile acid co-transporter inhibitor, or an ATP citrate lyase inhibitor. Other lipid
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`agents for possible use with the compounds include phytoestrogen compounds, beta(cid:173)
`
`lactam cholesterol absorption inhibitors, HDL upregulator such as LXR agonists, PPAR
`
`alpha-agonists and/or FXR agonists, LDL catabolism promoters, sodium-proton
`exchange inhibitors, LDL-receptor inducers, steroidal glycosides, anti-oxidants,
`
`isoniazid, HMG-CoA synthase inhibitors, lanosterol demethylase inhibitors, PPAR delta
`
`agonists, sterol regulating element binding protein-I (SREBP-1), and sphingolipids. The
`
`compounds may also be combined with anti-diabetic agents, such as PPAR gamma
`agonists and PPAR alpha/gamma dual agonists.
`
`[0013] U.S. Published Application No. 2005/0182103 describes substituted diphenyl
`
`pyridines that are antagonists and/or inverse agonists of CB1. These compounds may
`
`be combined with antipsychotic agents, cognition-enhancing agents, anti-migraine
`agents, anti-asthmatic agents, anti-inflammatory agents, anxiolytics, anti-Parkinson's
`
`agents, anti-epileptic agents, anorectic agents, serotonin reuptake inhibitors, and other
`
`anti-obesity agents. Use of the compounds to treat co-morbidities of obesity, such as
`
`dyslipidemia, is discussed.
`
`[0014] U.S. Published Application Nos. 2004/0214856, 2004/0214855, 2004/0214838,
`2004/0214837, and 2004/0157839 are related, and describe various compounds
`
`believed to be cannabinoid receptor ligands, more particularly CB1 antagonists. Other
`
`suitable pharmaceutical agents may be administered in combination with anti-obesity
`
`agents, anti-hypertensive agents, cannabinoid receptor ligands, including lipid-lowering
`agents, cholesterol biosynthesis inhibitors, and cholesterol absorption inhibitors. These
`
`other agents may include glitazones, HMG-CoA reductase inhibitors, HMG-CoA
`
`synthase inhibitors, HMG-CoA reductase or synthase gene expression inhibitors, CETP
`inhibitors, bile acid sequestrants, fibrates, ACAT inhibitors, squalene synthetase
`
`inhibitors, anti-oxidants, and nicotinic acid (niacin). Naturally occurring compounds
`(commonly called nutraceuticals) that act to lower plasma cholesterol levels may also
`
`be included, such as garlic extract, Hoodia plant extracts, and niacin.
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`[0015] U.S. Published Application No. 2002/0055539 relates to compositions and
`methods for treating or preventing cardiovascular conditions by intravascular
`administration of an omega fatty acid. The cardiovascular condition may be peripheral
`
`vascular disease. The compositions may include one or more omega-3 fatty acids, one
`
`or more omega-6 fatty acids, or a mixture of one or more omega-3 and one or more
`
`omega-6 fatty acids. In accordance with the methods of treatment, the composition is
`
`preferably administered intravascularly in close proximity to the site to be treated.
`
`[0016] There is clearly a great need in the art for compositions that are useful for
`treating dyslipidemia, particularly dyslipidemia that is present in obese patients, and
`
`patients with type II diabetes, high blood pressure, and/or metabolic syndrome.
`Methods of treating dyslipidemia ·using the formulations are also needed, particularly in
`
`patients with obesity, type II diabetes, high blood pressure, and/or metabolic syndrome.
`
`Summary of the Invention
`[0017] The present invention provides compositions comprising a CB1 antagonist and a
`dyslipidemic agent and/or metabolic regulator. Compositions of the invention are useful
`
`for treating various dyslipidemias, including hypertriglyceridemia, hypercholesteremia,
`
`and mixed dyslipidemia; vascular disease; artherosclerotic disease; and related
`conditions characterized by the presence of dyslipidemias, vascular disease, and/or
`
`atherosclerotic disease. These compositions of the invention may also be useful for
`treating obesity; preventing or reducing cardiovascular and vascular events; reducing
`
`insulin resistance, fasting glucose levels and postprandial glucose levels; treating and/or
`preventing diabetes and/or symptoms thereof; and reducing the incidence of and/or
`
`delaying the onset of type II diabetes and/or metabolic syndrome.
`
`[0018] The present invention also provides methods of treating various dyslipidemias,
`including hypertriglyceridemia, hypercholesteremia, and mixed dyslipidemia; treating
`
`vascular disease; treating artherosclerotic disease; treating or preventing conditions
`
`characterized by the presence of dyslipidemias, vascular disease, and/or atherosclerotic
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`disease; treating obesity; preventing or reducing cardiovascular and vascular events;
`
`reducing insulin resistance, fasting glucose levels and postprandial glucose levels;
`
`treating and/or preventing diabetes and/or symptoms thereof; and reducing the
`
`incidence of and/or delaying the onset of type II diabetes and/or metabolic syndrome.
`
`These diseases and conditions may be treated and/or prevented by administering a
`
`composition including a CB1 antagonist in combination with a dyslipidemic agent and/or
`
`a metabolic regulator. The CB 1 antagonist and dyslipidemic agent and/or metabolic
`
`regulator may be administered in the same composition, or concomitantly in separate
`
`compositions, as described herein.
`
`[0019] One embodiment of the present invention includes a combination product
`including one or more dyslipidemic agents selected from DPP4 inhibitors, MTP
`
`inhibitors, and omega-3 fatty acids, and one or more compounds that act as antagonists
`
`of CB1 receptors. Such a combination product may be provided, for example, in a unit
`
`dosage form. In some embodiments, such compositions are useful for treating various
`
`dyslipidemias, including hypertriglyceridemia, hypercholesteremia, and mixed
`
`dyslipidemia; treating vascular disease; treating artherosclerotic disease; treating or
`preventing conditions characterized by the presence of dyslipidemias, vascular disease,
`
`and/or atherosclerotic disease; treating obesity; preventing or reducing cardiovascular
`
`and vascular events; reducing insulin resistance, fasting glucose levels and postprandial
`
`glucose levels; treating and/or preventing diabetes and/or symptoms thereof; and
`reducing the incidence of and/or delaying the onset of type II diabetes and/or metabolic
`
`syndrome, wherein one or more dyslipidemic agents are combined with the CB1
`
`antagonist to provide specific therapeutic properties. According to some embodiments,
`
`the combination product further comprises one or more metabolic regulators.
`
`[0020] Another embodiment of the present invention includes a combination product
`including one or more PPAR agonists/antagonists and one or more compounds that act
`
`as an antagonist of CB1 receptors. Such a combination product may be provided, for
`example, in a unit dosage form. In some embodiments, such compositions are useful
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`for treating various dyslipidemias, including hypertriglyceridemia, hypercholesteremia,
`
`and mixed dyslipidemia; treating vascular disease; treating artherosclerotic disease;
`treating or preventing conditions characterized by the presence of dyslipidemias,
`
`vascular disease, and/or atherosclerotic disease; treating obesity; preventing or
`
`reducing cardiovascular and vascular events; reducing insulin resistance, fasting
`
`glucose levels and postprandial glucose levels; treating and/or preventing diabetes
`
`and/or symptoms thereof; and reducing the incidence of and/or delaying the onset of
`type II diabetes and/or metabolic syndrome, wherein one or more PPAR
`
`agonists/antagonists are combined with one or more CB 1 antagonists to provide
`
`specific therapeutic properties. According to some embodiments, the combination
`
`product further comprises one or more metabolic regulators.
`
`[0021] Another embodiment of the present invention includes a combination product
`including one or more metabolic regulators selected from sarsasapogenin, smilagenin,
`
`steroidal glycosides and extracts thereof, and extracts of Artemisia spp., and one or
`
`more compounds that act as an antagonist of CB1 receptors. Such a combination
`
`product may be provided, for example, in a unit dosage form. In some embodiments,
`
`such compositions are useful for treating various dyslipidemias, including
`
`hypertriglyceridemia, hypercholesteremia, and mixed dyslipidemia; treating vascular
`
`disease; treating artherosclerotic disease; treating or preventing conditions
`
`characterized by the presence of dyslipidemias, vascular disease, and/or atherosclerotic
`
`disease; treating obesity; preventing or reducing cardiovascular and vascular events;
`
`reducing insulin resistance, fasting glucose levels and postprandial glucose levels;
`
`treating and/or preventing diabetes and/or symptoms thereof; and reducing the
`
`incidence of and/or delaying the onset of type II diabetes and/or metabolic syndrome,
`
`wherein one or more metabolic regulators are combined with the CB1 antagonist to
`
`provide specific therapeutic properties. According to some embodiments, one or more
`dyslipidemic agents and/or PPAR agonists/antagonists may also be provided.
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`[0022] Another embodiment of the present invention includes methods of treating
`patients by administering compositions containing one or more dyslipidemic agents
`
`selected from omega-3 fatty acids, MTP inhibitors, and DPP4 inhibitors, and one or
`
`more compounds that act as antagonists of CB1 receptors. These methods provide an
`
`effective treatment for patients suffering from hypertriglyceridemia, hypercholesteremia,
`
`mixed dyslipidemia, vascular disease, artherosclerotic disease and/or related
`
`conditions. The methods also may be beneficially used to treat obesity, to prevent or
`reduce cardiovascular and vascular events, reduce insulin resistance, fasting glucose
`
`levels and postprandial glucose levels, treating and/or preventing diabetes and/or
`
`symptoms thereof, and/or to prevent and/or reduce the incidence of and/or the delay of
`
`onset of type II diabetes and/or metabolic syndrome. According to a preferred
`
`embodiment, the one or more dyslipidemic agents and one or more CB1 antagonists
`are provided for co-administration, or as unit doses, with one or more additional
`
`compounds that are also useful for treating dyslipidemia and any of the various
`
`conditions associated therewith. According to some embodiments, one or more
`metabolic regulators may also be administered.
`
`[0023] Another embodiment of the present invention includes methods of treating
`patients by administering compositions containing one or more metabolic regulators
`
`selected from sarsasapogenin, smilagenin, steroidal glycosides and extracts thereof,
`and extracts of Arlemisia spp., and one or more compounds that act as antagonists of
`
`CB1 receptors. These methods provide an effective treatment for patients suffering
`
`from hypertriglyceridemia, hypercholesteremia, mixed dyslipidemia, vascular disease,
`artherosclerotic disease and/or related conditions. The methods also may be
`
`beneficially used to treat obesity, to prevent or reduce cardiovascular and vascular
`
`events, reduce insulin resistance, fasting glucose levels and postprandial glucose
`
`levels, to treat and/or prevent diabetes and/or symptoms thereof, and/or to prevent
`and/or reduce the incidence of and/or the delay of onset of type II diabetes and/or
`
`metabolic syndrome. According to a preferred embodiment, the one or more metabolic
`
`regulators and one or more CB1 antagonists are provided for co-administration, or as
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`unit doses, with one or more additional compounds that are also useful for treating
`
`dyslipidemia and any of the various conditions associated therewith. According to
`
`some embodiments, one or more dyslipidemic agents and/or PPAR
`
`agonists/antagonists may also be administered.
`
`[0024] A further embodiment of the present invention includes methods of treating
`patients by administering one or more PPAR agonists/ antagonists and one or more
`
`compounds that act as antagonists of CB1 receptors. These methods may be useful for
`
`treating patients suffering from various dyslipidemias, including hypertriglyceridemia,
`
`hypercholesteremia, and mixed dyslipidemia; treating vascular disease; treating
`
`artherosclerotic disease; treating or preventing conditions characterized by the
`
`presence of dyslipidemias, vascular disease, and/or atherosclerotic disease; treating
`
`obesity; preventing or reducing cardiovascular and vascular events; reducing insulin
`
`resistance, fasting glucose levels and postprandial glucose levels; treating and/or
`
`preventing diabetes and/or symptoms thereof; and reducing the incidence of and/or
`
`delaying the onset of type II diabetes and/or metabolic syndrome. According to a
`
`preferred embodiment, the one or more PPAR agonists/antagonists and one or more
`
`CB1 antagonists are provided for co-administration, or as unit doses, with one or more
`
`additional compounds that are also useful for treating patients suffering from various
`dyslipidemias, including hypertriglyceridemia, hypercholesteremia, and mixed
`
`dyslipidemia; treating vascular disease; treating artherosclerotic disease; treating or
`
`preventing conditions characterized by the presence of dyslipidemias, vascular disease,
`and/or atherosclerotic disease; treating obesity; preventing or reducing cardiovascular
`
`and vascular events; reducing insulin resistance, fasting glucose levels and postprandial
`
`glucose levels; treating and/or preventing diabetes and/or symptoms thereof; and
`
`reducing the incidence of and/or delaying the onset of type II diabetes and/or metabolic
`
`syndrome. According to some embodiments, one or more metabolic regulators may
`
`also be administered.
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`[0025] The present invention also provides a composition comprising omega-3 fatty
`
`acids in combination with one or more compounds that antagonize the CB1 receptor, in
`
`order to provide an effective pharmaceutical treatment for dyslipidemia, which in some
`
`embodiments minimizes unwanted side effects and provides relief from other conditions
`
`commonly-associated with dyslipidemia, such as, but not limited to, obesity and type II
`
`diabetes. According to another embodiment, the composition including omega-3 fatty
`
`acids and a CB 1 receptor antagonist also includes another compound useful in treating
`
`various dyslipidemias, including hypertriglyceridemia, hypercholesteremia, and mixed
`
`dyslipidemia; treating vascular disease; treating artherosclerotic disease; treating or
`
`preventing conditions characterized by the presence of dyslipidemias, vascular disease,
`
`and/or atherosclerotic disease; treating obesity; preventing or reducing cardiovascular
`
`and vascular events; reducing insulin resistance, fasting glucose levels and postprandial
`
`glucose levels; treating and/or preventing diabetes and/or symptoms thereof; and
`
`reducing the incidence of and/or delaying the onset of type II diabetes and/or metabolic
`
`syndrome.
`
`[0026] One embodiment of the present invention provides a method of making a
`
`composition comprising one or more compounds that act as antagonists of CB1
`
`receptors, and one or more dyslipidemic agents and/or one or more metabolic
`
`regulators, for the treatment of subjects with dyslipidemia. Preferably, the dyslipidemic
`
`agents may be selected from omega-3 fatty acids, PPAR agonists/antagonists, MTP
`
`inhibitors, and DPP4 inhibitors. According to a presently preferred embodiment, the
`
`dyslipidemic agent comprises omega-3 fatty acids. Preferably, the metabolic regulators
`
`may be selected from sarsasapogenin, smilagenin, steroidal glycosides, and extracts of
`
`Artemisia spp.
`
`[0027] Another embodiment of the present invention is an oral formulation of one or
`
`more compounds that act as antagonists of CB1 receptors, and one or more
`
`dyslipidemic agents and/or one or more metabolic regulators. Preferably, the
`
`dyslipidemic agents may be selected from omega-3 fatty acids, PPAR
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`agonists/antagonists, MTP inhibitors, and DPP4 inhibitors. According to a presently
`
`preferred embodiment, the dyslipidemic agent comprises omega-3 fatty acids.
`Preferably, the metabolic regulators may be selected from sarsasapogenin, smilagenin,
`steroidal glycosides, and extracts of Artemisia spp.
`
`[0028J Another subject of the invention is a method of relieving dyslipidemia in a patient
`
`suffering therefrom, by providing a composition comprising one or more compounds that
`act as antagonists of CB1 receptors, and one or more dyslipidemic agents and/or one or
`
`more metabolic regulators, and thereafter administering the composition to